Treatment of prostate cancer

ABSTRACT

Methods for treating prostate cancer, including advanced prostate cancer, in a subject in need thereof, include administering once-daily to the subject, at least 80 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof. Another method includes: administering once-daily to the subject in need thereof, an oral load dose formulation having from 240 mg to 480 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and thereafter administering once-daily to the subject, an oral maintenance dose formulation having 80 mg to 160 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of of U.S. patentapplication Ser. No. 16/369,729, filed Mar. 29, 2019, which is acontinuation application of International Application No.PCT/EP2017/074849, filed Sep. 29, 2017, which claims priority to U.S.Provisional Application No. 62/402,150, filed Sep. 30, 2016, and U.S.Provisional Application No. 62/402,004, filed Sep. 30, 2016, thedisclosures of which are incorporated herein by reference in theirentirety.

FIELD

The present disclosure relates to methods for treating prostate cancer,including advanced prostate cancer and hormone dependent or sensitiveprostate cancer, in a subject by an oral formulation. It also includesthe treatment of men with castration-resistant prostate cancer. Inparticular, the present disclosure relates to methods for suppressingone or more sex hormones in a subject, by once-daily oral administrationof a dosage form. The present disclosure also relates to a dosage packhaving a separate oral load dose formulation and oral maintenance doseformulation.

BACKGROUND

Prostate cancer is the second most prevalent form of cancer in men andthe second leading cause of death due to cancer in men in the UnitedStates. According to the National Cancer Institute, approximately 2.9million men are currently living with prostate cancer in the UnitedStates, and approximately 180,000 men are newly diagnosed in the UnitedStates each year.

After diagnosis of prostate cancer, treatments generally includecombinations of surgery and radiation therapy, but androgen deprivationtherapies, or ADT, are also used. Prostate cancer is responsive tosurgical castration and the effectiveness of this therapy results fromthe elimination of androgens. An androgen may refer to any natural orsynthetic compound, usually a steroid hormone, which stimulates orcontrols the development and maintenance of male characteristics invertebrates by binding to androgen receptors. Androgens includetestosterone, dihydrotestosterone (DHT), dehydroepiandrosterone, andandrostenedione. Most prostate cancers are androgen dependent andandrogens, such as testosterone, promote the growth of cancerousprostate cells. ADT drastically reduces serum testosterone levels,blocks androgen receptor signaling, and delays prostate cancerprogression. ADT serves as alternative to surgical castration and isvaluable in the treatment of prostate cancer.

Castration by orchiectomy or a gonadotropin-releasing hormone (GnRH)agonist (GnRH receptor agonist) is the main mode of therapy forlocalized progressive and metastatic cancers, and GnRH agonists, such asleuprolide acetate, are widely used. When multiple doses of a GnRHagonist are administered, a temporary increase in gonadotropin secretionoccurs. That is followed by a decrease in responsiveness(desensitization) in the pituitary gland and a decrease in secretion ofthe pituitary sex hormones, such as luteinizing hormone (LH) andfollicle-stimulating hormone (FSH), which results in the decrease of sexhormones produced by the testes, such as testosterone and DHT. Theinitial increase in hormones caused by GnRH agonists leads to atemporary worsening of symptoms known as a clinical flare, such as anincrease in bone pain and, more seriously, spinal cord compression. Theeffectiveness of GnRH agonist therapy does not begin to appear untilabout 3 to 4 weeks after the initial dose. In addition, known GnRHagonists are peptides that are unable to be administered orally and mustbe administered subcutaneously (SC), intravenously (IV),intramuscularly, or intranasally. Often these GnRH agonists areadministered as depot formulation once every 1-3 months. Consequently,development is needed for a new treatment that is easy and convenient toadminister, does not cause clinical flare, and which allows forsuspension of treatment for a variety of time periods, and an increasein serum testosterone levels over a short period of time once treatmentis suspended.

BRIEF SUMMARY OF THE DISCLOSURE

One aspect of the disclosure relates to a method for treating prostatecancer in a subject in need of an increase in serum testosterone levelsto a level above 50 ng/dL, the method comprising administering to thesubject once-daily an oral formulation comprising about 80 mg to about480 mg of Compound 1:N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,wherein when the once-daily administration is suspended for a suspensionperiod, the subject experiences an increase of serum testosteronelevels.

Another aspect of the disclosure relates to a method for treatingprostate cancer in a subject in need thereof, the method comprisingadministering to the subject once-daily an oral formulation comprisingabout 80 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof; suspending administration ofthe oral formulation for a suspension period to allow for an increase ofserum testosterone levels; and resuming administering to the subjectonce-daily the oral formulation at the end of the suspension period.

One aspect of the disclosure relates to an oral formulation comprisingabout 80 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, for use in a method oftreating prostate cancer in a subject in need thereof.

Another aspect of the disclosure relates to an oral formulationcomprising about 80 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, for use in amethod for treating prostate cancer in a subject in need thereof, themethod comprising: administering the oral formulation to the subjectonce daily; suspending administration of the oral formulation for asuspension period to allow for an increase of serum testosterone levels;and resuming administering to the subject once daily the oralformulation at the end of the suspension period.

In certain embodiments of any of the foregoing or following, after thesuspension period, once-daily administration of the oral formulation ofthe disclosure is not resumed.

In certain embodiments of any of the foregoing or following, the serumtestosterone level increases to above medical castration level. In someembodiments, the serum testosterone level increases to greater thanabout 55 ng/dL or to greater than about 350 ng/dL. In certainembodiments, the serum testosterone level increases to about 300 ng/dLto about 600 ng/dL.

In some embodiments of any of the foregoing or following, the serumtestosterone level increases to the subject's serum testosterone levelprior to once-daily administration of the oral formulation of thedisclosure. In certain embodiments of any of the foregoing or following,the serum testosterone level increases to the subject's serumtestosterone level prior to once-daily administration of the oralformulation of the disclosure within 7 days of the beginning of thesuspension period. In certain embodiments of any of the foregoing orfollowing, the serum testosterone level increases to the subject's serumtestosterone level prior to once-daily administration of the oralformulation of the disclosure within 45 days of the beginning of thesuspension period.

In some embodiments of any of the foregoing or following, the prostatecancer is hormone dependent prostate cancer. In certain embodiments, theprostate cancer is advanced prostate cancer. In some embodiments, theprostate cancer is metastatic, non-metastatic, locally advanced,advanced hormone sensitive, advanced castration resistant, or recurrent.In certain embodiments, the prostate cancer is castration-resistantmetastatic prostate cancer. In some embodiments, the prostate cancer iscastration-resistant non-metastatic prostate cancer. In certainembodiments, the prostate cancer is hormone-sensitive metastaticprostate cancer. In some embodiments, the prostate cancer ishormone-sensitive non-metastatic prostate cancer.

In certain embodiments of any of the foregoing or following, saidadministering comprises administration once-daily of an oral load doseformulation of from about 240 mg to about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, for1-3 days at the beginning of treatment. In some embodiments, saidadministering comprises administration once-daily of an oral load doseformulation of from about 240 mg to about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, for1-3 days at the beginning of treatment after the suspension period. Incertain embodiments, said administering comprises administrationonce-daily of an oral maintenance dose formulation of from about 80 mgto about 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In certain embodiments of anyof the foregoing or following, the once-daily oral maintenance doseformulation administration begins on the day after administering thelast dose of the once-daily oral load dose formulation.

In certain embodiments of any of the foregoing or following, thesuspension period is up to 52 weeks, up to 36 weeks, up to 24 weeks, upto 12 weeks, up to 8 weeks, or up to 4 weeks.

In certain embodiments of any of the foregoing or following, thesuspension period is discontinued when the subject's prostate-specificantigen (PSA) level is ≥20% of the subject's PSA level of the nadirduring treatment. In some embodiments, the suspension period isdiscontinued when the subject's PSA level is ≥50% of the subject's PSAlevel prior to treatment. In certain embodiments, the suspension periodis discontinued when the subject's PSA level is greater than thesubject's PSA level at the beginning of the suspension period. Incertain embodiments, the suspension period is discontinued when thesubject experiences return of symptoms of prostate cancer. In someembodiments, the suspension period may be discontinued when thesubject's PSA level is ≥3 ng/mL, ≥10 ng/mL, ≥20 ng/mL, or ≥30 ng/mL.

In certain embodiments of any of the foregoing or following, the oralformulation is administered once-daily for 12 consecutive weeks orgreater, for 24 consecutive weeks or greater, for 48 consecutive weeksor greater, for 52 consecutive weeks or greater, for 72 consecutiveweeks or greater, or for 96 consecutive weeks or greater.

In certain embodiments of any of the foregoing or following, once-dailyadministration of an oral formulation of the disclosure is suspendedafter at least 24 consecutive weeks of treatment, at least 36consecutive weeks of treatment, or at least 52 consecutive weeks oftreatment.

In certain embodiments of any of the foregoing or following, the subjectis in need of an increase in serum testosterone levels due to anintercurrent illness, receiving radiation therapy, while bedridden,having suffered an injury, having a surgical procedure or other invasiveprocedure, or a desire for a period of restored sexual function. In someembodiments, the subject is in need of an increase in serum testosteronelevels due to an intercurrent illness or surgical or other invasiveprocedure with projected full recovery time of at least two weeks. Incertain embodiments, once-daily administration of the oral formulationof the disclosure is suspended prior to a surgical or other invasiveprocedure or radiation therapy. In some embodiments, once-dailyadministration of the oral formulation of the disclosure is suspendedafter or during the surgical or other invasive procedure, injury, orradiation therapy. In certain embodiments of any of the foregoing orfollowing, once-daily administration of the oral formulation of thedisclosure occurs prior to and during the surgical or other invasiveprocedure or radiation therapy and once-daily administration of the oralformulation of the disclosure is suspended after the surgery or otherinvasive procedure or radiation therapy. In some embodiments, thesurgical procedure is heart surgery, knee replacement, hip replacement,abdominal surgery, pelvic surgery, vascular surgery, spine surgery, oran emergency procedure due to injury. In certain embodiments of any ofthe foregoing or following, the subject is identified as at risk foracute postoperative frailty. In some embodiments, once-dailyadministration of the oral formulation of the disclosure is suspendedduring the intercurrent illness or while the subject is bedridden. Insome embodiments, once-daily administration of the oral formulation ofthe disclosure is suspended following an accident or injury requiringprolonged recovery. In some embodiments, once-daily once-dailyadministration of the oral formulation of the disclosure is suspendedfollowing a stroke, cerebral hemorrhage, myocardial infarction,congestive heart failure, hip fracture or other event resulting inlimited mobility and requiring prolonged recovery. In certainembodiments, once-daily administration of the oral formulation of thedisclosure resumes after the subject is recovered from the intercurrentillness, is no longer bedridden, has resumed normal activities of dailyliving, or has regained a normal level of function. In some embodiments,the invasive procedure is a colonoscopy, angioplasty, stent placement,endovascular coil placement, endovascular aneurysm repair, endoscopy,laparoscopy, arthroscopy, coronary catheterization, or anothercathether-based procedure.

In certain embodiments of any of the foregoing or following, the serumtestosterone level is above medical castration levels within 7 days ofthe suspension of once-daily administration of the oral formulation ofthe disclosure.

In certain embodiments of any of the foregoing or following, the oralload dose formulation comprises about 240 mg, about 360 mg, or about 480mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In certain such embodiments, the oral load doseformulation comprises about 360 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In certain embodiments of any of the foregoing or following, the oralmaintenance dose formulation comprises about 80 mg, about 120 mg, orabout 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In certain such embodiments,the oral maintenance dose formulation comprises about 120 mg of Compound1, or a corresponding amount of a pharmaceutically acceptable saltthereof.

In certain embodiments of any of the foregoing or following, the oralload dose formulation comprises about 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andis administered once on day 1 of treatment, and the oral maintenanceformulation comprises about 120 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, and isadministered once-daily.

In certain embodiments of any of the foregoing or following, the oralformulation comprises about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof.

In certain embodiments of any of the foregoing or following, theadministering is pre-prandial. In some embodiments, the administering isat least 1 hour before eating or at least 2 hours after eating. Incertain embodiments, the administering is at least 30 minutes beforeeating or while subject is fasting.

In certain embodiments of any of the foregoing or following, the oralformulation, oral load dose formulation and oral maintenance doseformulation are immediate release formulations.

In certain embodiments of any of the foregoing or following, the oralmaintenance dose formulation comprises 102 mg to 204 mg of mannitol, 6mg to 12 mg of hydroxypropyl cellulose, 10 mg to 20 mg of sodium starchglycolate, and 2 mg to 4 mg of magnesium stearate.

One aspect of the disclosure relates to any of the foregoing orfollowing methods or uses further comprising administering ananti-androgen. In certain such embodiments, the anti-androgen isselected from the group consisting of flutamide, nilutamide,bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrolacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide (fluridil), and cimetidine.

In certain embodiments of any of the foregoing or following methods oruses, the methods or uses further comprise administering a CYP17 lyaseinhibitor. In certain such embodiments, the CYP17 lyase inhibitor isabiraterone.

In certain embodiments of any of the foregoing or following, thesubject's serum testosterone level is suppressed prior to and after thesuspension of once-daily administration of the oral formulation of thedisclosure.

In certain embodiments of any of the foregoing or following, the methodor use does not comprise administration of an anti-androgen.

In certain embodiments of any of the foregoing or following, the methodor use does not comprise administration of prednisone. In someembodiments, the method or use further comprises administration ofprednisone.

In certain embodiments of any of the foregoing or following, the methodor use further comprises suspending once-daily administration of theoral formulation of the disclosure for a subsequent suspension periodafter completion of the suspension period and resumption of once-dailyadministration of the oral formulation of the disclosure. In someembodiments, the subsequent suspension period occurs at least 12 weeksafter resuming once-daily administration of the oral formulationcomprising about 80 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In certain embodiments of any of the foregoing or following, withinabout 4 to about 8 days of first administering once-daily the oralformulation, or oral load dose formulation and oral maintenance doseformulation, the serum testosterone levels in the subject are at orbelow medical castration level. In some embodiments, within 4 days offirst administering once-daily the oral formulation, or oral load doseformulation and oral maintenance dose formulation, the serumtestosterone levels in the subject are at or below medical castrationlevel.

One aspect of the disclosure relates to use of Compound 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of prostate cancer. In certain suchembodiments, the prostate cancer is hormone dependent prostate cancer,advanced prostate cancer, metastatic, non-metastatic, locally advanced,advanced hormone sensitive, advanced castration resistant, recurrent,castration-resistant metastatic prostate cancer, castration-resistantnon-metastatic prostate cancer, hormone-sensitive metastatic prostatecancer, or hormone-sensitive non-metastatic prostate cancer. In someembodiments, the medicament comprises 80 mg to about 480 mg of Compound1, or a corresponding amount of the pharmaceutically acceptable saltthereof.

Other objects and advantages of the present disclosure will becomeapparent from the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically depicts mean serum testosterone concentrations for atreatment period of 28 days in accordance with Example 6.

FIG. 2 is a table of individual changes in serum testosteroneconcentration of each Compound 1 dose level in accordance with Example 6in which the serum testosterone concentrations are graphically depictedin FIGS. 1 and 7.

FIG. 3 graphically depicts mean serum LH concentrations for a treatmentperiod (Part A) in accordance with Example 6.

FIG. 4 graphically depicts mean serum FSH concentrations for a treatmentperiod (Part A) in accordance with Example 6.

FIG. 5 graphically depicts mean serum dihydrotestosterone (DHT)concentrations for a treatment period (Part A) in accordance withExample 6.

FIG. 6 graphically depicts mean serum sex hormone-binding globulin(SHBG) concentrations for a treatment period (Part A) in accordance withExample 6.

FIG. 7 graphically depicts mean serum testosterone concentrations for atreatment period (Part B) in accordance with Example 6.

FIGS. 8A and 8B graphically depict mean serum testosteroneconcentrations for a treatment period (Part B) for 80 mg Compound 1 and120 mg Compound 1 in accordance with Example 6.

FIG. 9 graphically depicts mean serum LH concentrations for a treatmentperiod (Part A) in accordance with Example 6.

FIG. 10 graphically depicts mean serum FSH concentrations for atreatment period (Part A) in accordance with Example 6.

FIG. 11 graphically depicts mean serum DHT concentrations for atreatment period (Part A) in accordance with Example 6.

FIG. 12 graphically depicts mean serum sex hormone-binding globulin(SHGB) concentrations at maintenance doses of 80 mg or 120 mg or atreatment period (Part A) in accordance with Example 6.

FIG. 13 is a table of serum prostate-specific antigen (PSA) and changefrom the subject's serum PSA level prior to treatment commencing witheach Compound 1 dose level (Part A) in accordance with Example 6.

FIG. 14 is a table of serum PSA and change from the subject's serum PSAlevel prior to treatment commencing with each Compound 1 dose level(Part B) in accordance with Example 6.

FIGS. 15A, 15B, and 15C graphically depict mean plasma concentrations ofunchanged Compound 1 for a treatment period (Part A) in accordance withExample 6.

FIG. 16 is a table of plasma pharmacokinetic (PK) parameters of Compound1 for a treatment period (Part A) in accordance with Example 6.

FIGS. 17A and 17B graphically depict mean plasma trough concentrationsof unchanged Compound 1 for a treatment period (Part B) in accordancewith Example 6.

FIGS. 18A and 18B graphically depict mean plasma concentration-timeprofiles of Compound 1 after single oral dose administration (Part 1) inaccordance with Example 7.

FIG. 19 graphically depicts mean plasma concentration-time profiles ofCompound 1 after single oral dose administration (Part 1) under fastedand fed conditions in accordance with Example 7.

FIG. 20 is a table of mean plasma and urine pharmacokinetic (PK)parameters following a single oral Compound 1 dose administration(Part 1) in accordance with Example 7.

FIGS. 21A and 21B graphically depict mean plasma concentration-timeprofiles of Compound 1 after single and multiple oral doseadministration (Part 2) in accordance with Example 7.

FIG. 22 is a table of mean plasma and urine Compound 1 pharmacokinetic(PK) parameters obtained after day 1 after oral Compound 1administration (Part 2) in accordance with Example 7.

FIG. 23 is a table of mean plasma and urine Compound 1 pharmacokinetic(PK) parameters obtained after day 14 after multiple oral Compound 1administration (Part 2) in accordance with Example 7.

FIG. 24 is a table of mean serum LH concentration-time data (IU/L) forthe treatment period (Part 1) in accordance with Example 7.

FIG. 25 graphically depicts mean time-course of serum testosteronelowering following a single dose administration of Compound 1 (Part 1)in accordance with Example 7.

FIG. 26 is a table of mean serum testosterone concentration-time data(nmol/L) for the treatment period (Part 1) in accordance with Example 7.

FIG. 27 is a table of mean serum FSH concentration-time data (IU/L) forthe treatment period (Part 1) in accordance with Example 7.

FIG. 28 is a table of mean serum dihydrotestosterone (DHT)concentration-time data (nmol/L) for the treatment period (Part 1) inaccordance with Example 7.

FIG. 29 is a table of mean serum LH concentration-time data (IU/L) forthe treatment period (Part 2) in accordance with Example 7.

FIG. 30 graphically depicts mean time-course of serum testosteronelowering following a multiple dose administration of Compound 1 (Part 2)in accordance with Example 7.

FIGS. 31A and 31B are a table of mean serum testosteroneconcentration-time data (nmol/L) for the treatment period (Part 2) inaccordance with Example 7.

FIG. 32 is a table of mean serum FSH concentration-time data (IU/L) forthe treatment period (Part 2) in accordance with Example 7.

FIG. 33 is a table of mean serum dihydrotestosterone (DHT)concentration-time data (nmol/L) for the treatment period (Part 2) inaccordance with Example 7.

FIG. 34 is a table of mean serum LH concentration-time data (IU/L) forthe treatment period (Part 3) in accordance with Example 7.

FIG. 35 graphically depicts mean time-course of serum testosteronelowering following a multiple dose administration of Compound 1 (Part 3)in accordance with Example 7.

FIG. 36 is a table of mean serum testosterone concentration-time data(nmol/L) for the treatment period (Part 3) in accordance with Example 7.

FIG. 37 is a table of mean serum FSH concentration-time data (IU/L) forthe treatment period (Part 3) in accordance with Example 7.

FIG. 38 is a table of mean serum dihydrotestosterone (DHT)concentration-time data (nmol/L) for the treatment period (Part 3) inaccordance with Example 7.

FIG. 39 is a table of mean serum LH concentration-time data (IU/L) forthe treatment period (Part 4) in accordance with Example 7.

FIG. 40 graphically depicts mean time-course of serum testosteronelowering following a multiple dose administration of Compound 1 (Part 4)in accordance with Example 7.

FIG. 41 is a table of mean serum testosterone concentration-time data(nmol/L) for the treatment period (Part 4) in accordance with Example 7.

FIG. 42 is a table of mean serum FSH concentration-time data (IU/L) forthe treatment period (Part 4) in accordance with Example 7.

FIG. 43 is a table of mean serum dihydrotestosterone (DHT)concentration-time data (nmol/L) for the treatment period (Part 4) inaccordance with Example 7.

FIGS. 44A, 44B, 44C, and 44D graphically depict time-course of serumtestosterone suppression following treatment (Part 2) with Compound 1 inhealthy men for 14 days in accordance with Example 7.

FIG. 45 graphically depicts the correlation between serum testosteronesuppression and Compound 1 steady state exposure in healthy men (Part 2)in accordance with Example 7.

FIGS. 46A, 46B, 46C, and 46D graphically depict the time-course of serumtestosterone suppression following treatment (Parts 3 and 4) withCompound 1 in healthy men for 28 days in accordance with Example 7.

FIGS. 47A and 47B graphically depict the percent of subjects reachingserum testosterone below castration levels after 28 days of treatment(Parts 3 and 4) with Compound 1 in accordance with Example 7.

FIG. 48 graphically depicts the correlation between serum testosteronesuppression and Compound 1 steady state exposure in healthy men (Parts 3and 4) in accordance with Example 7.

FIG. 49 is a table of castration and profound castration rate data forCompound 1 compared to degarelix in accordance with Example 9.CI=confidence interval, Q4W=once every 4 weeks, QD=daily. (a) Castrationrate was defined as the estimated proportion of patients who have serumtestosterone concentrations <50 ng/dL at all scheduled visits Week 5,Day 1 to specific timepoint (Week 25, Day 1). (b) The 2-sided 95% CI wascalculated using the normal approximation method, if the number ofnon-castration patients was =5 in any treatment arm, the exact CI waspresented. (c) Profound castration rate was defined as the estimatedproportion of patients who had serum testosterone concentrations <20ng/dL at all scheduled visits Week 13, Day 1 through specific timepoint(Week 25, Day 1).

FIG. 50 graphically depicts a Kaplan-Meier survival curve for time toserum testosterone recovery (i.e., the subject's serum testosteronelevel prior to treatment commencing or >280 ng/dL) in accordance withExample 9. ADT=androgen deprivation therapy, QD=daily, SC=subcutaneous.(a) Time to serum testosterone recovery was defined as the time from 1day after the last dose of Compound 1 or 4 weeks plus 1 day after thelast dose of degarelix to serum testosterone recovery. Serumtestosterone recovery was defined as back to the subject's serumtestosterone level prior to treatment commencing or >280 ng/dL whicheveroccurs first. It was censored for patients starting alternative ADTwithout recovery at the last serum testosterone lab assessment beforethe start of ADT.

FIG. 51 is a table of time to serum testosterone recovery (i.e., thesubject's serum testosterone level prior to treatment commencing or >280ng/dL) in accordance with Example 9. CI=confidence interval,Max=maximum, Min=minimum, NE=not estimable, Q4W=once every 4 weeks,QD=daily. * indicates a censored observation. (a) Time to serumtestosterone recovery was defined as the time from 1 day after the lastdose of Compound 1 or 4 weeks plus 1 day after the last dose ofdegarelix to serum testosterone recovery. Serum testosterone recoverywas defined as back to the subject's serum testosterone level prior totreatment commencing or >280 ng/dL whichever occurs first. It wascensored for patients starting alternative ADT without recovery at thelast serum testosterone lab assessment before the start of ADT. (b)Probability of event (n=number of subjects at risk). (c) 4, 8 or 12weeks from 1 day after the last dose of Compound 1 or 4, 8 or 12 weeksplus 1 day after the last dose of degarelix. (d) The 2-sided 95% CI forproportion was calculated using the normal approximation method.

FIG. 52 graphically depicts the PSA reduction provided in Example 8.

FIG. 53 graphically depicts the recovery of serum testosterone levelsprovided in Example 9.

FIG. 54 graphically depicts the clinical trial detailed in Example 11.Compound 1 will be dosed daily (Day 1 to Week 48, Day 7). Leuprolideacetate will be dosed every 12 weeks (Day 1; Week 13, Day 1; Week 25,Day 1; and Week 37, Day 1). *The +60 days and +90 days testosteronerecovery visits will happen with a subset of patients.

DETAILED DESCRIPTION

Disclosed herein are methods of using an orally active GnRH antagonist(GnRH receptor antagonist), Compound 1, or a pharmaceutically acceptablesalt thereof, once-daily for the treatment of prostate cancer. Theprostate cancer can be hormone dependent prostate cancer, advancedprostate cancer, advanced hormone sensitive prostate cancer, metastatic,non-metastatic, locally advanced, advanced hormone dependent, advancedcastration resistant, recurrent, castration-resistant metastaticprostate cancer, castration-resistant non-metastatic prostate cancer,hormone-sensitive metastatic prostate cancer, or hormone-sensitivenon-metastatic prostate cancer. After administration to a subject,formulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, rapidly inhibit production of sex hormones, such astestosterone, LH, and FSH, and are not associated with an initialaggravation of symptoms, also known as clinical or hormonal flares.

Unlike GnRH agonists such as leuprolide acetate, Compound 1, or apharmaceutically acceptable salt thereof, is present in an oralformulation and is not a depot, or a slow-release formulation and, oncetreatment is suspended, hormone levels increase and may return to thesubject's serum hormone levels prior to treatment commencing (i.e.,baseline levels) after once-daily administration of Compound 1, or apharmaceutically acceptable salt thereof, is discontinued, therebyproviding more control for patients and their physicians. Thus, incontrast to a treatment that uses depot injections, the treatmentmethods and uses of this disclosure allow for suspension periods inwhich subjects can stop treatment for a period of time and later restarttreatment with no adverse effects. Suspension of treatment can beplanned (e.g., in advance of, during or after a scheduled surgical orinvasive procedure (e.g., knee replacement surgery or colonoscopy)) orcan be implemented after the subject experiences, for example,intercurrent illness or injury. In either scenario (planned orunplanned), increasing the serum testosterone levels aids in recovery orhelps to maintain the subject's physical health.

Additionally, in some patients receiving GnRH antagonists or GnRHagonists, even after treatment is discontinued for significant timeperiods, pre-treatment levels of serum testosterone are not achieved.Miranda et al., The Journal of Urology, May 16, 2017, Volume 197, Issue4, e1221-e1222 (noting 23% of patients receiving ADT with a GnRH agonistmaintained medical castration testosterone levels at 24 months after ADTcessation); Tsumura et al., World J. Radiol., Dec. 28, 2015; 7(12):494-500 (noting five years after the cessation of GnRH agonist therapy,approximately one-fifth of patients still had medical castrationtestosterone levels). One of the advantages of Compound 1, or apharmaceutically acceptable salt thereof, is that, as shown in Example 9and FIGS. 50 and 53, 43% of subjects achieve pre-treatment serumtestosterone levels or a serum testosterone level at or above 280 ng/dLby 12 weeks versus only 5.3% with degarelix.

The disclosure provides methods and uses for treating prostate cancer ina subject in need thereof comprising administering, once-daily,formulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof. Subjects treated once-daily with oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,experience an increase in serum testosterone levels after the last doseof the formulation comprising Compound 1, or a pharmaceuticallyacceptable salt thereof. Accordingly, the disclosure provides methods ofusing oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, for treating prostate cancer in a subject inneed of an increase in serum testosterone levels to a level above 50ng/dL. Once-daily administration of formulations comprising Compound 1,or a pharmaceutically acceptable salt thereof, can be suspended for asuspension period, leading to an increase in the subject's serumtestosterone levels shortly after the beginning of the suspensionperiod. For example, for most subjects, serum testosterone levels willincrease within 1 week of beginning a suspension period. An increase ina subject's serum testosterone level can be very beneficial for subjectsexperiencing an intercurrent illness, receiving radiation therapy, whilebedridden, having suffered an injury, having a surgical procedure orother invasive procedure, or a desire for a period of restored sexualfunction (e.g., 25^(th) wedding anniversary). Higher serum testosteronelevels can be beneficial in such subjects because testosterone has ananabolic effect, helping to rebuild tissues, increase weight and musclemass, and promote growth and mineralization of bone. Treatment can alsobe suspended to improve the subject's quality of life and energy levels;to help with healing after injury, illness, surgery, or radiationtherapy; to aid subjects in remaining in control of their lifestyles;and to assist in regaining strength and mobility after intercurrentillness. Even before serum testosterone levels reach the subject's serumtestosterone level prior to treatment commencing, the benefit ofincreased serum testosterone compared to a medical castration level maybe important in a subject's recovery from, for example, surgery, such asknee replacement or hip surgery (whether planned or unplanned). Thecontribution of testosterone to rebuilding tissue and increasing musclemass can be a factor for successful post-surgery physical therapy andregaining range of movement, mobility and strength. Once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, can resume at the end of thesuspension period. Alternatively, once-daily administration of oralformulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, does not necessarily resume after suspension of once-dailyadministration, for example, if prostate-specific antigen (PSA) levelsremain at an acceptable level during the suspension period.

Upon initial treatment or resumption of administration of Compound 1, ora pharmaceutically acceptable salt thereof, after a suspension period,serum testosterone levels typically fall to at or below medicalcastration levels within about 4 to about 8 days of first administeringonce-daily an oral formulation of the disclosure. This is in contrastwith leuprolide and other GnRH agonists. If a subject stops and restartstreatment with leuprolide, or other GnRH agonists, it may take up to onemonth to observe a decrease in the subject's serum testosterone levels.Furthermore, the maximum decline in PSA, or PSA nadir, occurs morerapidly with once-daily administration of Compound 1, or apharmaceutically acceptable salt thereof, than with GnRH agonists.Once-daily administration of Compound 1, or a pharmaceuticallyacceptable salt thereof, after a suspension period, also results inrapid (within days) and complete suppression of FSH unlike the GnRHagonists. There is a correlation between higher FSH levels and theprogression of prostate cancer, as FSH stimulates FSH receptorsexpressed on the endothelial cells of tumor blood vessels in prostatecancer specimens. Further, patients with low FSH levels have asignificantly longer time to castration resistance.

These advantages of the present methods and uses are important both inthe treatment setting, for example, where a subject may be receivingradiation treatment or where there is the occurrence of a condition orprocedure unrelated to the prostate cancer treatment. For example, asnoted previously consider a subject undergoing prostate cancer treatmentwho is involved in a car accident. Whether or not a surgical procedureis required to aid in recovery from the car accident, higher serumtestosterone levels will aid in the subject's recovery, such as inrebuilding damaged tissues or promoting the mineralization of bone inthe case of fractures. Unlike in a treatment regimen involving a depotformulation, which is injected and requires a long period of time for asubject's serum testosterone levels to rise even after the nominaltreatment period is complete, the present methods and uses allow forsuspension of treatment by stopping the once-daily administration of theoral formulations, leading to an immediate rise in serum testosteronelevels, without adverse effects in response to unexpected events.Additionally, where upcoming surgeries may be planned, for example a hipor knee replacement, the treatment can be suspended either shortly priorto or at the time of surgery to ensure optimal recovery of the patientafter surgery and potentially better outcomes due to higher levels ofthe anabolic hormone testosterone. The methods and uses disclosed hereinmay allow for resumption of once-daily administration of Compound 1, ora pharmaceutically acceptable salt thereof, during the post-operativerecovery stage if a subject's prostate cancer begins to worsen orspread. Upon resumption of administration of Compound 1, or apharmaceutically acceptable salt thereof, after a suspension period fora surgery, serum testosterone levels typically fall to at or belowmedical castration levels within about 4 to about 8 days of firstadministering once-daily an oral formulation of the disclosure. As itmay take up to one month to observe a decrease in a subject's serumtestosterone levels after administering depot formulations of GnRHagonists, treatments involving these agonists may not have as muchflexibility as treatments involving once-daily administration ofCompound 1, or a pharmaceutically acceptable salt thereof. The maximumdecline in PSA, or PSA nadir, may also occur more rapidly withonce-daily administration of Compound 1, or a pharmaceuticallyacceptable salt thereof, after a suspension period than with GnRHagonists. Once-daily administration of Compound 1, or a pharmaceuticallyacceptable salt thereof, after a suspension period, may result in rapid(within days) and complete suppression of FSH unlike the GnRH agonists.

The intermittent therapy allowed by the methods, uses, and formulationsof this disclosure may prevent the change from hormone dependent toandrogen independent prostate cancer. Androgen independence may be anintrinsic, but dormant, property of some prostate cancer cells that isactivated in response to androgen deprivation. The Compound 1, or apharmaceutically acceptable salt thereof, intermittent therapy disclosedherein could be dosed so that a complete and continuous androgendeprivation does not happen, possibly preventing androgen independence.Rather than having a steady low level of serum testosterone, Compound 1,or a pharmaceutically acceptable salt thereof, can allow fluctuationsback and forth (many peaks and valleys) with testosterone. “Intermittenttreatment,” intermittent therapy,” or “intermittent dosing” may refer toon-again, off-again treatment or a “drug holiday.” An example ofintermittent treatment is stopping once-daily administration of oralformulations of the disclosure once the PSA drops to a very low leveland if the PSA level begins to rise, restarting once-dailyadministration. Another form of intermittent therapy using the claimedmethods and uses may employ therapy for fixed periods of time, forexample, 6 months on followed by 6 months off.

Compound 1, or a pharmaceutically acceptable salt thereof, has a fasteronset of action than currently available GnRH agonists, and unlikeavailable peptide GnRH agonists that are given either subcutaneously orintranasally, Compound 1 is a non-peptide preparation that may beadministered orally and once-daily. When compared to GnRH agonists, suchas leuprolide acetate, which is typically administered as a depotformulation, Compound 1, or a pharmaceutically acceptable salt thereof,offers several advantages. Such advantages may include, but are notlimited to, oral administration, rapid onset of serum testosteronesuppression within four days, rapid onset of serum FSH suppression,rapid PSA depression, absence of clinical flare, no need foranti-androgen therapy to protect the patient from clinical flaresymptoms. The ability to suspend treatment for periods of time can leadto an increase in serum testosterone levels shortly after treatment issuspended and may also return serum testosterone to the subject's serumtestosterone level prior to treatment commencing after treatment issuspended, depending on the suspension period, and each of theseoutcomes may quickly result in improvements in quality of life, healing,and energy levels.

Compound 1, or a pharmaceutically acceptable salt thereof, also offersadvantages over other GnRH antagonists. Once-daily oral administrationof formulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, allows hormone levels, such as serum testosterone levels,to return to the subject's serum hormone levels prior to treatmentcommencing more rapidly than a GnRH antagonist depot formulation, suchas degarelix, after discontinuation. The option of increased serumtestosterone levels, including a return to the subject's serumtestosterone level prior to treatment commencing, is desirable forpatients wanting to eliminate any unwanted effects of hormonesuppression. The more rapid return of hormonal levels to the subject'sserum hormone levels prior to treatment commencing is also advantageousin the restoration of energy levels and strength in men, for example,for the reasons such as described above. However, when the symptoms ormarkers (e.g., PSA levels) of the prostate cancer indicate a resumptionof treatment is advisable, once-daily administration of Compound 1, or apharmaceutically acceptable salt thereof, can resume at short notice,with a rapid onset of action, and without a clinical flare.

Provided herein is the use of oral formulations comprising Compound 1,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treatment according to any of methods described herein.Provided also are oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

Further embodiments of the present disclosure are described hereinafter,in which some, but not all, embodiments of the disclosure areillustrated.

Each embodiment disclosed herein may be used individually or incombination with any other embodiment disclosed herein.

Publications, patents, and published patent applications referred to inthis application are specifically incorporated by reference herein.

Compounds

As used herein, Compound 1, namelyN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,is represented by the formula:

Compound 1 and pharmaceutical compositions including Compound 1 can beproduced by methods described in U.S. Pat. Nos. 7,300,935, 8,058,280,9,346,822, 9,758,528, 8,735,401, and WO 2016136849, the disclosures ofwhich are herein incorporated by reference.

In some embodiments, Compound 1 is a pharmaceutically acceptable salt.“Physiologically acceptable,” “pharmaceutically acceptable,” or“pharmacologically acceptable” compounds and compositions may includematerials which are not biologically, or otherwise, undesirable. Forexample, the material may be administered to an individual withoutcausing any substantially undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained. In certain such embodiments, the pharmaceuticallyacceptable salt of Compound 1 is a pharmaceutically acceptable acidaddition salt. Such salts include, but are not limited to, salts withinorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, and the like), and salts with organicacids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like).

Throughout the present disclosure, amounts of Compound 1 disclosed referto the amount of Compound 1 free form present in the formulation. Theterm “corresponding amount” as used herein refers to the amount of apharmaceutically acceptable salt of Compound 1 required to obtain theamount of Compound 1 free form recited in the formulation. It would beclear to one of skill in the art how to calculate the “correspondingamount” of the salt of a compound, such as the corresponding amount ofthe pharmaceutically acceptable salt of Compound 1, taking into accountthe difference in molecular weight between the free form of a compoundand a salt form. For example, 80.0 mg of compound free base, wouldcorrespond to 84.7 mg of the HCl salt.

Compound 1 has been characterized as an orally active, nonpeptide, GnRHantagonist. Compound 1 has been shown to antagonize GnRH through theGnRH receptors, which are present in the pituitary anterior lobebasophiles (secretory cells), and inhibits the GnRH-stimulated secretionof LH and FSH from these cells. As a result, the drug decreases bloodconcentrations of hormones, including testosterone. Compound 1, or apharmaceutically acceptable salt thereof, improves clinical symptomsobserved in patients with prostate cancer. Administration of oralformulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, also causes a rapid decline in serum PSA levels. AsCompound 1 is a GnRH antagonist, it does not cause clinical flare andhas a faster onset of action than GnRH agonists. Unlike GnRH agonists,Compound 1 is not a peptide preparation.

Therapeutic Uses and Methods of Treatment

Disclosed herein are methods of using an orally active, once-dailyadministered, GnRH antagonist, Compound 1, or a pharmaceuticallyacceptable salt thereof, for the treatment of prostate cancer.

The present disclosure provides oral formulations comprising at least 80mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, that can be employed in methods and uses fortreating prostate cancer in a subject in need thereof. “Prostate cancer”may capture any cancer of the prostate, such as those described herein.Most prostate cancer is adenocarcinoma, but rarely can also includetransitional cell (urothelial) cancer, squamous cell, small cell,carcinoid, or sarcomas. Prostate cancer can spread beyond the prostate(e.g., advanced prostate cancer) or it can be non-metastatic.“Non-metastatic prostate cancer” may refer to prostate cancer that hasnot spread from the primary site of the prostate and may behormone-sensitive. Hormonal therapy is used to reduce the serumtestosterone levels in prostate cancer. Hormonal therapy can also beused to reduce the serum PSA and FSH levels in prostate cancer. A“patient” or a “subject” may refer to a mammal or a non-mammal. Examplesof mammals include, but are not limited to, any member of the classMammalia: humans, non-human primates such as chimpanzees, and other apesand monkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. Examples of non-mammals include, but are not limited to, birds,fish and the like. In some embodiments of the present disclosure, themammal is a human. In some embodiments of the present disclosure, thepatient or subject is a human man.

In some embodiments of the methods and uses described herein, theprostate cancer is hormone dependent prostate cancer. “Hormone dependentprostate cancer,” “hormone sensitive prostate cancer,” “androgendependent prostate cancer,” or “androgen sensitive prostate cancer” mayrefer to prostate cancer needing relatively high levels of androgens togrow early in its development. Such prostate cancer may be referred toas androgen/hormone dependent or androgen/hormone sensitive becausetreatments that decrease androgen levels or block androgen activity caneffectively inhibit its growth.

In some embodiments of the methods and uses described herein, theprostate cancer is advanced prostate cancer. Prostate cancer istypically considered “advanced” if it has spread beyond the prostategland and the area around the prostate. It may spread to nearby tissues,lymph nodes, bones, or other parts of the body. When it spreads totissues directly adjacent to the prostate gland, it is often referred toas “locally advanced prostate cancer.” When it spreads beyond thetissues directly adjacent to the prostate gland, it is typicallyreferred to as “metastatic prostate cancer.” Metastatic prostate cancertypically may have spread to the bone, lung, liver, brain, lymph nodesoutside the pelvis, or other organs, and may be hormone-sensitive. Thefollowing types of prostate cancer are also generally considered“advanced”: PSA biochemical relapse following primary surgical orradiation therapy of curative intent; newly diagnosed metastaticprostate cancer; advanced localized disease for which immediateradiation or surgical therapy is not indicated, or men whose diseaseprogresses after prostatectomy or radiation. The clinical recurrence ofadvanced prostate cancer occurs when it is associated with symptoms.Therefore, “advanced” prostate cancer may be present with or withoutevidence on diagnostic imaging tests and with or without clinicalsymptoms. The treatment methods and uses of this disclosure includepalliative treatment of advanced prostate cancer.

In some embodiments of the methods and uses described herein, theprostate cancer is advanced hormone sensitive prostate cancer. “Advancedhormone dependent prostate cancer,” “advanced hormone sensitive prostatecancer,” “advanced androgen dependent prostate cancer,” or “advancedandrogen sensitive prostate cancer” as used herein may refer to prostatecancer that has spread beyond the prostate gland and the area around theprostate. The growth of prostate cancer is suppressed or the cancer mayeven shrink when androgen levels are suppressed (e.g., hormonal therapythat lowers serum testosterone below castration levels <50 ng/dL).

In some embodiments of the methods and uses described herein, theprostate cancer is locally advanced, advanced castration resistant, orrecurrent. “Locally advanced prostate cancer” may refer to cancer thathas started to break out of the prostate, or has spread to the area justoutside, or nearby, the prostate. It may also be characterized as stageT3 or T4 prostate cancer. It may have spread to one or more of e.g., theprostate capsule, the seminal vesicles, the pelvic lymph nodes, thebladder, and the back passage (rectum). “Advanced castration-resistantprostate cancer” or “advanced hormone-resistant prostate cancer” mayrefer to castration-resistant prostate cancer that has spread beyond theprostate gland and the area around the prostate. This type of cancercontinues to grow and progress even when androgen levels in the body areextremely low or undetectable. “Recurrent prostate cancer” may refer toprostate cancer that has been detected or has returned following initialtreatment, such as after surgery, radiation therapy, and/or hormonetherapy. Recurrent prostate cancer may have a biochemical and/orclinical recurrence. Some patients may only have a rise in PSA level asevidence of the recurrent prostate cancer (biochemical recurrence) andothers will have evidence of recurrent prostate cancer on x-rays andscans (clinical recurrence). “Biochemical recurrence” may refer to thereturn of the prostate cancer after initial treatment, but the returncannot be measured by standard imaging methods. Therefore, prostatecancer may be present with or without evidence on diagnostic imagingtests and with or without clinical symptoms. The return of the prostatecancer is identified by a rise in PSA as determined by a blood test. Thecriteria for is biochemical recurrence may include a rise in PSA of“nadir+2 ng/mL” for relapse after radiation therapy, >0.2 ng/mL ifrecurrent after prostatectomy, and >2 ng/mL if recurrent after all othertreatments. “Clinical recurrence” may refer to the return of clinicalsymptoms associated with growth or spread of prostate cancer afterinitial treatment of prostate cancer.

In some embodiments of the methods and uses described herein, theprostate cancer is castration-resistant prostate cancer. In someembodiments of the methods and uses described herein, the prostatecancer is castration-resistant metastatic prostate cancer. In someembodiments of the methods and uses described herein, the prostatecancer is castration-resistant non-metastatic prostate cancer.“Castration-resistant prostate cancer” or “hormone-resistant prostatecancer” may refer to prostate cancer that continues to grow even whenandrogen levels in the body are extremely low or undetectable. Forexample, with castration-resistant prostate cancer, PSA may increase orthe cancer may show other signs of growing even after using hormonetherapy to bring serum testosterone to castration levels (<50 ng/dL).For castration-resistant prostate cancer, hormonal therapy (e.g.,suppression of serum testosterone levels) is continued, and additionaltherapies are added to the treatment protocol in addition to thecontinued administration of drugs used to lower serum testosterone.Castration-resistant prostate cancer may be either metastatic(castration-resistant metastatic prostate cancer) or non-metastatic(castration-resistant non-metastatic prostate cancer) prostate cancer.“Metastatic castration resistant prostate cancer” or“castration-resistant metastatic prostate cancer” may refer to prostatecancer that has spread beyond the prostate and continues to grow andprogress (including but not limited to a rise in PSA) in the setting ofsuppressed androgen levels (i.e., hormonal therapy that lowers serumtestosterone below castration levels <50 ng/dL). In some embodiments,once-daily administration of an oral formulation comprising Compound 1,or a pharmaceutically acceptable salt thereof, reduces serum FSH levelsand, therefore, may reduce the rate of subjects who developcastration-resistant prostate cancer. In some embodiments, once-dailyadministration of an oral formulation comprising Compound 1, or apharmaceutically acceptable salt thereof, reduces serum FSH levels and,therefore, may slow the development of castration-resistant prostatecancer. In some embodiments of the methods and uses described herein,the prostate cancer is hormone-sensitive metastatic prostate cancer. Insome embodiments of the methods and uses described herein, the prostatecancer is hormone-sensitive non-metastatic prostate cancer.

In some embodiments of the methods and uses described herein, theprostate cancer is hormone naïve advanced prostate cancer. “Hormonenaïve advanced prostate cancer” may be subdivided into two diseasestates: biochemical recurrence or traditional metastatic prostate cancerand may be characterized by no prior hormonal therapy or androgendeprivation therapy (ADT).

In some embodiments, the oral formulations of the methods and usesdescribed herein comprise about 80 mg to about 480 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof. Asused herein, “oral formulation” encompasses the terms “oral load doseformulation,” “oral load dosage,” “oral load dose,” “oral maintenancedose formulation,” “oral maintenance dosage,” and the like, unlessclearly dictated otherwise by context. An “oral load dose formulation,”“oral load dosage,” or “oral load dose” is an initial dose of a Compound1, or a pharmaceutically acceptable salt thereof, that may be given atthe beginning of a course of treatment before changing to a differentmaintenance dose. As described herein, it is typically a larger initialdose of Compound 1, or a pharmaceutically acceptable salt thereof, orseries of such doses given to rapidly achieve a therapeuticallyeffective amount of drug in the body. A “therapeutically effectiveamount” may refer to an amount of a compound sufficient to treat aspecified disorder or disease or one or more of its symptoms and/or toprevent the occurrence of the disease or disorder. For example, atherapeutically effective dose for prostate cancer treatment includeswhere the treatment brings about an amelioration of one or more symptomsof the prostate cancer, slows the progression of the prostate cancer,results in remission, etc. An “oral maintenance dose formulation,” “oralmaintenance dosage,” or “oral maintenance dose” is the dose of Compound1, or a pharmaceutically acceptable salt thereof, given after a certainperiod of taking the load dosage and is typically a lower amount ofCompound 1, or a pharmaceutically acceptable salt thereof, than the loaddosage yet maintains the desired therapeutic effect.

In some embodiments, the oral formulations of the methods and usesdescribed herein comprise about 80 mg to about 160 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral formulations of the methods and usesdescribed herein comprise about 120 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral formulations of the methods and uses describedherein comprise about 360 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof. In some embodiments, theoral formulations of the methods and uses described herein compriseabout 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralformulations of the methods and uses described herein comprise about 180mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof.

The methods and uses described herein also include treating prostatecancer in a subject in need thereof by administering to the subjectonce-daily for at least 12 consecutive weeks, an oral formulationcomprising at least 80 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In certain such embodiments,the oral formulation comprises about 120 mg, about 180 mg, about 240 mg,or about 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In certain such embodiments,the oral formulation comprises about 120 mg or about 360 mg of Compound1, or a corresponding amount of a pharmaceutically acceptable saltthereof. The methods and uses described herein also include treatingprostate cancer in a subject in need thereof by administering to thesubject once-daily for at least 4 consecutive weeks, at least 8consecutive weeks, at least 12 consecutive weeks, at least 16consecutive weeks, at least 20 consecutive weeks, or at least 24consecutive weeks an oral formulation comprising at least 80 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof.

Several benefits may result from treating prostate cancer byadministering Compound 1, or a pharmaceutically acceptable salt thereof,thereby suppressing one or more sex hormones, to a subject in need oftreatment as described herein. “Suppression” as used herein may occur byinhibiting the production of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH) by the pituitary gland, a hormonerequired by the testes to make testosterone and other androgens or sexhormones. Follicle-stimulating hormone (FSH) stimulates FSH receptorsexpressed on the endothelial cells of tumor blood vessels in prostatecancer specimens. FSH signaling in prostate cancer may contribute to theprogression of castration resistant prostate cancer. Suppression ofserum testosterone levels may mean that the testes are not producingtestosterone at the levels normally observed in the absence of treatmentfor an oral formulation comprising Compound 1, or a pharmaceuticallyacceptable salt thereof. The degree of suppression is measured by serumtestosterone, or other sex hormone, levels in the blood. Sex hormonesmay refer to any glandular secretions that are responsible forcontrolling sexual development and reproductive function in males. Suchsex hormones include, for example, testosterone, dihydrotestosterone,follicle-stimulating hormone (FSH), LH, GnRH, androsterone, and inhibin.In accordance with this disclosure, one or more sex hormones, includingtestosterone, FSH, and LH, may be suppressed by the once-dailyadministration of Compound 1, or a pharmaceutically acceptable saltthereof, to a subject having prostate cancer. In particular, medicalcastration levels of less than or equal to 50 ng/dL (1.73 nmol/L) serumtestosterone may be achieved and maintained from day 14 to day 28 afterbeginning once-daily administration. Also, following once-dailyadministration of an oral formulation of 180 mg on day 1 of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,medical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone may be achieved within 24 to 48 hours.Further, following once-daily administration of a single oral load doseformulation of 360 mg and once-daily administration of oral maintenancedose formulations of 120 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, for 48 consecutive weeks,medical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone are achieved by the beginning of week 5 andmaintained through the end of week 48. Further, following once-dailyadministration of a single oral load dose formulation of 240 mg andonce-daily administration of oral maintenance dose formulations of 120mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 48 consecutive weeks, medical castrationlevels of less than or equal to 50 ng/dL (1.73 nmol/L) serumtestosterone are achieved by the beginning of week 5 and maintainedthrough the end of week 48. As used herein, “medical castration”generally refers to serum testosterone levels of about ≤50 ng/dL and“profound castration” generally refers to serum testosterone levels ofabout ≤20 ng/dL.

In accordance with this disclosure, methods and uses are provided forsuppressing one or more sex hormones, including testosterone, LH, andFSH, in a subject having prostate cancer. Additionally, in accordancewith this disclosure, methods and uses are provided for suppressingserum PSA levels. In some embodiments, the methods and uses include:administering to the subject once-daily for at least one day, an oraldosage form that includes at least one oral load dose formulation,wherein the oral load dose formulation comprises about 240 mg to about480 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof; and administering once-daily to the subject forat least 4 consecutive weeks, at least 8 consecutive weeks, at least 12consecutive weeks, at least 16 consecutive weeks, at least 20consecutive weeks, or at least 24 consecutive weeks, an oral maintenancedose formulation, in which the oral maintenance dose formulationcomprise about 80 mg to about 160 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the methods and uses include administering to the subjectonce-daily for at least 24 consecutive weeks, in an oral maintenancedose formulation, at least 80 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In the methods and uses of this disclosure, serum testosterone may besuppressed in the subject to a level less than or equal to 50 ng/dL(1.73 nmol/L) or less than or equal to 20 ng/dL (0.69 nmol/L). In someembodiments, following once-daily administration of an oral formulationof 180 mg on day 1 of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, medical castration levels ofless than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone may beachieved within 24 to 48 hours after commencing administration. In someembodiments, following once-daily administration of a single oral loaddose formulation of 360 mg and oral maintenance dose formulations of 120mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 48 consecutive weeks, medical castrationlevels of less than or equal to 50 ng/dL (1.73 nmol/L) serumtestosterone may be achieved by the beginning of week 5 and maintainedthrough the end of week 48. In some embodiments, following once-dailyadministration of a single oral load dose formulation of 240 mg and oralmaintenance dose formulations of 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, for48 consecutive weeks, medical castration levels of less than or equal to50 ng/dL (1.73 nmol/L) serum testosterone may be achieved by thebeginning of week 5 and maintained through the end of week 48.

The treatment methods and uses of this disclosure may provide fast onsetand fast offset for subjects. With respect to offset, unlike GnRHagonists, such as leuprolide acetate, Compound 1, or a pharmaceuticallyacceptable salt thereof, is neither a depot or a slow-releaseformulation, and hormone levels, particularly serum testosterone levels,increase and may return to the subject's serum hormone levels prior totreatment commencing more rapidly after once-daily administration isdiscontinued, providing more control and treatment options for patientsand their physicians. For example, a more rapid increase of hormonelevels, including increases in serum testosterone levels, in some casesto the subject's serum hormone levels prior to treatment commencing(pre-treatment levels), may be advantageous in the management of anintercurrent illness, among other conditions and procedures, and for therestoration of sexual function and energy levels in men. Methods anduses described herein may permit more rapid recovery from short-termmedical castration, when used for neoadjuvant/adjuvant therapy orintermittent ADT. As noted previously, this flexibility is important inboth the treatment setting, for example, where a subject may bereceiving radiation treatment or where there is the occurrence of acondition or procedure unrelated to the prostate cancer treatment. Forexample, as noted previously consider a subject undergoing prostatecancer treatment who is involved in a car accident. Whether or not asurgical procedure is required to aid in recovery from the car accident,higher serum testosterone levels will aid in the subject's recoverybecause testosterone has an anabolic effect, helping to rebuild tissuesand increase weight and muscle mass. Unlike in a treatment regimeninvolving a depot formulation, the present methods and uses allow forsuspension of treatment without adverse effects in response tounexpected events (e.g., illness, injury, etc.). Additionally, whereupcoming surgeries may be planned, for example a hip or kneereplacement, the treatment may be suspended either shortly prior to orat the time of surgery to ensure optimal recovery of the patient aftersurgery and potentially better outcomes due to higher serum testosteronelevels.

Subjects undergoing treatment in accordance with this disclosure may beable to remain in control of their lifestyle and quality of life. Incontrast to conventional treatments which use depot injections,treatment with formulations of this disclosure allows for suspensionperiods, or intermittent treatment, in which subjects can stop treatmentfor a period of time and later restart treatment with no adverseeffects, including no incidence of clinical flare. “Clinical” or“hormonal flare” may refer to a temporary increase in serum testosteronelevels from complete serum testosterone suppression levels in the bodycaused by certain types of hormone therapy (e.g., androgen deprivationtherapy) used to treat prostate cancer. Clinical flare can be serious innature, for example, causing exacerbation of bone pain and urinaryproblems. The treatment methods and uses of this disclosure may providea desirable quick on/off option for subjects. The treatment methods anduses of this disclosure allow maintenance of sexual activity by subjectsat certain times during the treatment period. Increases in serumtestosterone levels can also promote an increase in energy levels, whichmay have a positive impact on the subject's (and the subject's family's)quality of life. For example, for important life events (e.g., attendingone's daughter's wedding, walking her down the aisle, and dancing withthe mother of the bride or celebrating an important weddinganniversary), the present methods and uses can incorporate suspensionperiod allowing for increased energy levels or improvement in sexualfunction and therefore greater enjoyment of such events, without thepotential adverse impact on the control of the prostate cancer relatedto the clinical flare associated with restarting treatment after thesuspension period.

The disclosure provides methods of using oral formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof, for treatingprostate cancer in a subject in need of an increase in serumtestosterone levels to a level above 50 ng/dL. The disclosure alsoprovides methods and uses for treating prostate cancer in a subject inneed thereof comprising administering once-daily formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof. Once-dailyadministration of formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, can be suspended for asuspension period, leading to an increase in the subject's serumtestosterone levels. In certain embodiments, once-daily administrationof oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, resumes at the end of the suspension period. Insome embodiments, once-daily administration of oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,does not resume after it is suspended.

The present disclosure further provides that, after suspendingonce-daily administration of oral formulations of the disclosure for asuspension period, the subject may experience an increase in serumtestosterone levels. In some embodiments after stopping once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, for a suspension period, asubject's serum testosterone level may increase within 1 day of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increasewithin 2 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase within 3 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase within 4 daysof the beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase within 5 days of the beginning of the suspension period. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase within 6 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase within 7 daysof the beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase within 10 days of the beginning of the suspension period.

During a suspension period, a subject's serum testosterone level mayincrease to the subject's serum testosterone level prior to once-dailyadministration of an oral formulation of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof. With respectto offset, after stopping once-daily administration for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulation ofthe disclosure within 4 weeks, or within 8 weeks, or within 12 weeks, orwithin 16 weeks, or within 24 weeks, after the last dose administeredprior to the suspension period. In some embodiments, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to once-daily administration of the oral formulation of thedisclosure within 4 weeks to 12 weeks after the last dose. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof, within 1 dayof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations within 2 days of the suspension of administration. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 3 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 4 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 5 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 6 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 7 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 8 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 9 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 10 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 15 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 20 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 30 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 35 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 40 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 45 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 50 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 55 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 60 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 65 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 70 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 75 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 80 days of the suspension of administration. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, the serum testosterone level mayincrease to the subject's serum testosterone level prior toadministration of the oral formulations of the disclosure within 85 daysof the suspension of administration. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, the serum testosterone level may increase to thesubject's serum testosterone level prior to administration of the oralformulations of the disclosure within 90 days of the suspension ofadministration. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, the serum testosterone level may increase to the subject's serumtestosterone level prior to administration of the oral formulations ofthe disclosure within 95 days of the suspension of administration. Insome embodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, the serumtestosterone level may increase to the subject's serum testosteronelevel prior to administration of the oral formulations of the disclosurewithin 100 days of the suspension of administration.

The disclosure provides for increases in a subject's serum testosteronelevel to greater than medical castration levels. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure comprising Compound 1, or a pharmaceutically acceptable saltthereof, for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 1 day ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 2 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 3 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 4 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 5 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 6 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 7 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 10 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 15 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 20 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 25 days ofthe beginning of the suspension period. In some embodiments afterstopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than medical castration levels within 30 days ofthe beginning of the suspension period.

In some embodiments after stopping once-daily administration of oralformulations of the disclosure comprising Compound 1, or apharmaceutically acceptable salt thereof, for a suspension period, asubject's serum testosterone level may increase to greater than about 55ng/dL within 1 day of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 2 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 3 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 4 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 5 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 6 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 7 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 10 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 15 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 20 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 25 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than about 55 ng/dLwithin 30 days of the beginning of the suspension period.

Normal serum testosterone levels for European and American men, 19 to 39years, are variable and are reported to be between about 250 ng/dL toabout 920 ng/dL (see, The Journal of Clinical Endocrinology &Metabolism, Volume 102, Issue 4, 1 Apr. 2017, Pages 1161-1173).Suspension of once-daily administration of the oral formulations of thedisclosure may allow for increases in a subject's serum testosteronelevels to a range between about 250 ng/dL to about 920 ng/dL, or to“normal” serum testosterone levels. The Endocrine Society recommendsabout 300 ng/dL as the lower limit of “normal” serum testosteronelevels. Other medical societies recommend 150 ng/dL, 200 ng/dL, or 230ng/dL as the lower limit of “normal” serum testosterone levels. Themethods and uses of the disclosure may allow for a return to “normal”serum testosterone levels. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof, for asuspension period, a subject's serum testosterone level may increase togreater than or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL,about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL,about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL,about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dLwithin 1 day of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 2 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 3days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 4 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 5 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 6days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 7 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 10 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 15days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 20 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 25 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 30days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 35 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 40 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 45days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 50 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 55 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 60days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 65 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 70 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 75days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 80 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 85 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL,about 80 ng/dL, about 85 ng/dL, about 90 ng/dL, about 95 ng/dL, about100 ng/dL, about 150 ng/dL, about 200 ng/dL, about 250 ng/dL, about 280ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600 ng/dL within 90days of the beginning of the suspension period. In some embodimentsafter stopping once-daily administration of oral formulations of thedisclosure for a suspension period, a subject's serum testosterone levelmay increase to greater than or about 60 ng/dL, about 65 ng/dL, about 70ng/dL, about 75 ng/dL, about 80 ng/dL, about 85 ng/dL, about 90 ng/dL,about 95 ng/dL, about 100 ng/dL, about 150 ng/dL, about 200 ng/dL, about250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL, or about 600ng/dL within 95 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to greater than or about 60 ng/dL,about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng/dL, about 85ng/dL, about 90 ng/dL, about 95 ng/dL, about 100 ng/dL, about 150 ng/dL,about 200 ng/dL, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL,about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL,about 550 ng/dL, or about 600 ng/dL within 100 days of the beginning ofthe suspension period. In some embodiments after stopping once-dailyadministration of oral formulations of the disclosure for a suspensionperiod, a subject's serum testosterone level may increase to greaterthan or about 350 ng/dL after the beginning of the suspension period.

In some embodiments after stopping once-daily administration of oralformulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, for a suspension period, a subject's serum testosteronelevel may increase to about 50 ng/dL to about 100 ng/dL, about 100 ng/dLto about 150 ng/dL, about 150 ng/dL to about 200 ng/dL, about 200 ng/dLto about 250 ng/dL, about 250 ng/dL to about 300 ng/dL, about 300 ng/dLto about 350 ng/dL, about 350 ng/dL to about 400 ng/dL, about 400 ng/dLto about 450 ng/dL, about 450 ng/dL to about 500 ng/dL, about 500 ng/dLto about 550 ng/dL, about 550 ng/dL to about 600 ng/dL, or about 300ng/dL to about 600 ng/dL within 1 day of the beginning of the suspensionperiod. In some embodiments after stopping once-daily administration oforal formulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 2 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 3 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 4 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 5 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 6 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 7 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 10 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 15 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 20 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 25 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 30 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 35 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 40 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 45 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 50 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 50 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 60 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 65 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 70 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 75 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 80 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 85 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 90 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 50 ng/dL to about 100 ng/dL, about 100 ng/dL to about 150 ng/dL,about 150 ng/dL to about 200 ng/dL, about 200 ng/dL to about 250 ng/dL,about 250 ng/dL to about 300 ng/dL, about 300 ng/dL to about 350 ng/dL,about 350 ng/dL to about 400 ng/dL, about 400 ng/dL to about 450 ng/dL,about 450 ng/dL to about 500 ng/dL, about 500 ng/dL to about 550 ng/dL,about 550 ng/dL to about 600 ng/dL, or about 300 ng/dL to about 600ng/dL within 95 days of the beginning of the suspension period. In someembodiments after stopping once-daily administration of oralformulations of the disclosure for a suspension period, a subject'sserum testosterone level may increase to about 50 ng/dL to about 100ng/dL, about 100 ng/dL to about 150 ng/dL, about 150 ng/dL to about 200ng/dL, about 200 ng/dL to about 250 ng/dL, about 250 ng/dL to about 300ng/dL, about 300 ng/dL to about 350 ng/dL, about 350 ng/dL to about 400ng/dL, about 400 ng/dL to about 450 ng/dL, about 450 ng/dL to about 500ng/dL, about 500 ng/dL to about 550 ng/dL, about 550 ng/dL to about 600ng/dL, or about 300 ng/dL to about 600 ng/dL within 100 days of thebeginning of the suspension period. In some embodiments after stoppingonce-daily administration of oral formulations of the disclosure for asuspension period, a subject's serum testosterone level may increase toabout 300 ng/dL to about 600 ng/dL after the beginning of the suspensionperiod.

In some embodiments, a subject's serum testosterone level may besuppressed prior to and after the suspension of administration (e.g.,the serum testosterone level is below the medical castration level,profound medical castration level, significantly lower than thesubject's level prior to treatment (e.g., less than 50% of pre-treatmentlevel, less than 40%, less than 30%, less than 20%, less than 10%, lessthan 5%, or less than 1%)).

With respect to onset, the present disclosure also provides for resumingonce-daily administration of an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure after a suspension period to achieve a return to medicalcastration levels of serum testosterone. As noted previously, resumingonce-daily administration with Compound 1, or a pharmaceuticallyacceptable salt thereof, does not include the disadvantageous clinicalflare associated with GnRH agonists and therefore should not lead toworsening of symptoms or erosion of prior gains in treatment as wouldrestarting treatment after a suspension period when treating with GnRHagonists. In some embodiments, within about 4 to about 8 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure after a suspension period, the serum testosterone levelsin the subject may be at or below medical castration level. In someembodiments, within 4 days of first administering once-daily an oralformulation of the disclosure or an oral load dose formulation and anoral maintenance dose formulation of the disclosure after a suspensionperiod, the serum testosterone levels in the subject may be at or belowmedical castration level. In some embodiments, within 5 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure after a suspension period, the serum testosterone levelsin the subject may be at or below medical castration level. In someembodiments, within 6 days of first administering once-daily an oralformulation of the disclosure or an oral load dose formulation and anoral maintenance dose formulation of the disclosure after a suspensionperiod, the serum testosterone levels in the subject may be at or belowmedical castration level. In some embodiments, within 7 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure after a suspension period, the serum testosterone levelsin the subject may be at or below medical castration level. In someembodiments, within 8 days of first administering once-daily an oralformulation of the disclosure or an oral load dose formulation and anoral maintenance dose formulation of the disclosure after a suspensionperiod, the serum testosterone levels in the subject may be at or belowmedical castration level. In some embodiments, within 3 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure after a suspension period, the serum testosterone levelsin the subject may be at or below medical castration level.

In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 180 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 24 hours to 48 hours aftercommencing administration. In some embodiments, after resumingonce-daily administration of an oral formulation of the disclosurecomprising about 180 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, after a suspension period,serum testosterone levels in a subject may be at or below medicalcastration level within 3 days after commencing administration. In someembodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 180 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 4 days after commencingadministration. In some embodiments, after resuming once-dailyadministration of an oral formulation of the disclosure comprising about180 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, after a suspension period, serum testosteronelevels in a subject may be at or below medical castration level within 5days after commencing administration. In some embodiments, afterresuming once-daily administration of an oral formulation of thedisclosure comprising about 180 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, after a suspensionperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 6 days after commencing administration.In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 180 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 1 week after commencingadministration.

In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, after a suspension period, serum testosterone levels in asubject may be at or below medical castration level within 24 hours to48 hours after commencing administration. In some embodiments, afterresuming once-daily administration of an oral formulation of thedisclosure comprising about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 3 days after commencingadministration. In some embodiments, after resuming once-dailyadministration of an oral formulation of the disclosure comprising about80 mg to about 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, after a suspension period,serum testosterone levels in a subject may be at or below medicalcastration level within 4 days after commencing administration. In someembodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, after a suspension period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration. In some embodiments, after resumingonce-daily administration of an oral formulation of the disclosurecomprising about 80 mg to about 160 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, after a suspensionperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 6 days after commencing administration.In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, after a suspension period, serum testosterone levels in asubject may be at or below medical castration level within 1 week aftercommencing administration.

In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 120 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 24 hours to 48 hours aftercommencing administration. In some embodiments, after resumingonce-daily administration of an oral formulation of the disclosurecomprising about 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, after a suspension period,serum testosterone levels in a subject may be at or below medicalcastration level within 3 days after commencing administration. In someembodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 120 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 4 days after commencingadministration. In some embodiments, after resuming once-dailyadministration of an oral formulation of the disclosure comprising about120 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, after a suspension period, serum testosteronelevels in a subject may be at or below medical castration level within 5days after commencing administration. In some embodiments, afterresuming once-daily administration of an oral formulation of thedisclosure comprising about 120 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, after a suspensionperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 6 days after commencing administration.In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure comprising about 120 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,after a suspension period, serum testosterone levels in a subject may beat or below medical castration level within 1 week after commencingadministration.

In some embodiments, following administration of an oral load doseformulation of the disclosure comprising 240 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period (e.g., atleast 4 consecutive weeks or greater, at least 8 consecutive weeks orgreater, at least 12 consecutive weeks or greater, at least 16consecutive weeks or greater, at least 20 consecutive weeks or greater,24 consecutive weeks or greater, 36 consecutive weeks or greater, 48consecutive weeks or greater, 52 consecutive weeks or greater, 72consecutive weeks or greater, or 96 consecutive weeks or greater),medical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone may be achieved within 24 to 48 hours aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 3 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 240 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, on once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 4 days after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 240 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 6 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 240 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 1 week after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 240 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 2 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 3 weeks after commencing administration and maintaineduntil the end of administration. In some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 weeks aftercommencing administration and maintained until the end ofadministration.

In some embodiments, following administration of an oral load doseformulation of the disclosure comprising 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period (e.g., atleast 4 consecutive weeks or greater, at least 8 consecutive weeks orgreater, at least 12 consecutive weeks or greater, at least 16consecutive weeks or greater, at least 20 consecutive weeks or greater,24 consecutive weeks or greater, 36 consecutive weeks or greater, 48consecutive weeks or greater, 52 consecutive weeks or greater, 72consecutive weeks or greater, or 96 consecutive weeks or greater),medical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone may be achieved within 24 to 48 hours aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 3 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 360 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, on once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 4 days after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 360 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 6 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 360 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowmedical castration level within 1 week after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 360 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 2 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below medical castrationlevel within 3 weeks after commencing administration and maintaineduntil the end of administration. In some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 weeks aftercommencing administration and maintained until the end ofadministration.

In some embodiments, following administration of an oral load doseformulation of the disclosure comprising 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period (e.g., atleast 4 consecutive weeks or greater, at least 8 consecutive weeks orgreater, at least 12 consecutive weeks or greater, at least 16consecutive weeks or greater, at least 20 consecutive weeks or greater,24 consecutive weeks or greater, 36 consecutive weeks or greater, 48consecutive weeks or greater, 52 consecutive weeks or greater, 72consecutive weeks or greater, or 96 consecutive weeks or greater),profound castration levels of less than or equal to 20 ng/dL (1.73nmol/L) serum testosterone may be achieved within 24 to 48 hours aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below profound castrationlevel within 3 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 360 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, on once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowprofound castration level within 4 days after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 360 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below profound castrationlevel within 6 days after commencing administration and maintained untilthe end of administration. In some embodiments, following administrationof an oral load dose formulation of the disclosure comprising 360 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, once-daily for 1-3 days at the beginning of treatmentafter a suspension period, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, serum testosterone levels in a subject may be at or belowprofound castration level within 1 week after commencing administrationand maintained until the end of administration. In some embodiments,following administration of an oral load dose formulation of thedisclosure comprising 360 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 2 weeksafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure comprising 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,starting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, serumtestosterone levels in a subject may be at or below profound castrationlevel within 3 weeks after commencing administration and maintaineduntil the end of administration. In some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 4 weeksafter commencing administration and maintained until the end ofadministration.

In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure after a suspension period, median timefrom administration of the first oral formulation after the suspensionperiod to PSA nadir may be less than 5 weeks, less than 6 weeks, lessthan 7, weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks,less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, lessthan 18 weeks, less than 19 weeks, less than 20 weeks, less than 21weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks, orless than 25 weeks. In some embodiments, after resuming once-dailyadministration of an oral formulation of the disclosure after asuspension period, median time from administration of the first oralformulation after the suspension period to PSA nadir may be about 5weeks to about 10 weeks, about 5 weeks to about 15 weeks, about 5 weeksto about 20 weeks, about 5 weeks to about 25 weeks, about 10 weeks toabout 15 weeks, about 10 weeks to about 20 weeks, about 10 weeks toabout 25 weeks, or about 15 weeks to about 20 weeks. In someembodiments, after resuming once-daily administration of an oralformulation of the disclosure after a suspension period, median timefrom administration of the first oral formulation after the suspensionperiod to PSA nadir may be about 10 weeks to about 20 weeks. In someembodiments, after resuming once-daily administration of oralformulations of the disclosure for 4 weeks following a suspensionperiod, serum PSA levels are reduced by greater than or equal to about5%, greater than or equal to about 10%, greater than or equal to about20%, greater than or equal to about 30%, greater than or equal to about40%, greater than or equal to about 50%, greater than or equal to about60%, greater than or equal to about 70%, greater than or equal to about80%, or greater than or equal to about 90% of the subject's serum PSAlevels prior to treatment commencing. In some embodiments, afterresuming once-daily administration of oral formulations of thedisclosure for 4 weeks following a suspension period, serum PSA levelsare reduced by greater than or equal to about 50% of the subject's serumPSA levels prior to treatment commencing.

In some embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment after a suspension period, and once-daily administration ofan oral maintenance dose formulation of the disclosure starting on theday after administering the last dose of the oral load dose formulation,and continuing for a set treatment period, median time from commencingtreatment to PSA nadir may be less than 5 weeks, less than 6 weeks, lessthan 7, weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks,less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, lessthan 18 weeks, less than 19 weeks, less than 20 weeks, less than 21weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks, orless than 25 weeks. In some embodiments, following administration of anoral load dose formulation of the disclosure once-daily for 1-3 days atthe beginning of treatment after a suspension period, and once-dailyadministration of an oral maintenance dose formulation of the disclosurestarting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period, median timefrom commencing treatment to PSA nadir may be about 5 weeks to about 10weeks, about 5 weeks to about 15 weeks, about 5 weeks to about 20 weeks,about 5 weeks to about 25 weeks, about 10 weeks to about 15 weeks, about10 weeks to about 20 weeks, about 10 weeks to about 25 weeks, or about15 weeks to about 20 weeks. In some embodiments, followingadministration of an oral load dose formulation of the disclosureonce-daily for 1-3 days at the beginning of treatment after a suspensionperiod, and once-daily administration of an oral maintenance doseformulation of the disclosure starting on the day after administeringthe last dose of the oral load dose formulation, and continuing for aset treatment period, median time from commencing treatment to PSA nadirmay be about 10 weeks to about 20 weeks. In some embodiments, 4 weeksafter commencing administration of an oral load dose formulation of thedisclosure once-daily for 1-3 days after a suspension period, andonce-daily administration of an oral maintenance dose formulation of thedisclosure starting on the day after administering the last dose of theoral load dose formulation, serum PSA levels are reduced by greater thanor equal to about 5%, greater than or equal to about 10%, greater thanor equal to about 20%, greater than or equal to about 30%, greater thanor equal to about 40%, greater than or equal to about 50%, greater thanor equal to about 60%, greater than or equal to about 70%, greater thanor equal to about 80%, or greater than or equal to about 90% of thesubject's serum PSA levels prior to treatment commencing. In someembodiments, 4 weeks after commencing administration of an oral loaddose formulation of the disclosure once-daily for 1-3 days after asuspension period, and once-daily administration of an oral maintenancedose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, serum PSAlevels are reduced by greater than or equal to about 50% of thesubject's serum PSA levels prior to treatment commencing.

In some embodiments, after resuming once-daily administration of an oralformulation of the disclosure for 1 week, 4 weeks, 12 weeks, 24 weeks,or 48 weeks after a suspension period, serum FSH levels may be less thanor equal to about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, orabout 1.2 mIU/mL. In certain such embodiments, once-daily administrationof oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, may result in sustained suppression of serumFSH levels. Normal FSH levels in adult males are typically between 1.5to 12.4 mIU/mL, but are elevated in subjects with prostate cancer. Insome embodiments, after resuming once-daily administration of an oralformulation of the disclosure for 1 week after a suspension period,serum FSH levels may be less than or equal to about 7.2 mIU/mL, about4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL. In some embodiments,resuming once-daily administration of an oral formulation of thedisclosure for 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks after asuspension period may suppress serum FSH levels by greater than or equalto about 80% or about 90% of the subject's serum FSH levels prior totreatment commencing.

In some embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment after a suspension period, and once-daily administration ofan oral maintenance dose formulation of the disclosure starting on theday after administering the last dose of the oral load dose formulation,serum FSH levels may be less than or equal to about 7.2 mIU/mL, about4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL 1 week, 4 weeks, 12weeks, 24 weeks, or 48 weeks after commencing treatment. In certain suchembodiments, once-daily administration of oral formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof, may result insustained suppression of serum FSH levels. In some embodiments,following administration of an oral load dose formulation of thedisclosure once-daily for 1-3 days at the beginning of treatment after asuspension period, and once-daily administration of an oral maintenancedose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, serum FSHlevels may be less than or equal to about 7.2 mIU/mL, about 4.8 mIU/mL,about 2.4 mIU/mL, or about 1.2 mIU/mL 1 week after commencing treatment.In some embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment after a suspension period, and once-daily administration ofan oral maintenance dose formulation of the disclosure starting on theday after administering the last dose of the oral load dose formulation,serum FSH levels may be suppressed by greater than or equal to about 80%or about 90% of the subject's serum FSH levels prior to treatmentcommencing 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks aftercommencing treatment.

Because of the return to serum testosterone levels to a level above 50ng/dL after the last dose of an oral formulation comprising Compound 1,or a pharmaceutically acceptable salt thereof, and the rapid onset ofthe oral formulations of the disclosure once once-daily administrationis restarted after a suspension period, administration may be suspendedfor a suspension period as necessary to allow for an increase in serumtestosterone levels. In certain embodiments, the subject is in need ofan increase in serum testosterone levels to a level above 50 ng/dL.Increases in serum testosterone level may be needed due to anintercurrent illness, receiving radiation therapy, while bedridden,having suffered an injury, having a surgical procedure or other invasiveprocedure, or a desire for a period of restored sexual function. An“intercurrent illness” may refer to an illness occurring during thecourse of another illness, not related to the primary illness process(e.g., the illness is not prostate cancer or a symptom of prostatecancer but can be, for example pneumonia, etc.). In some embodiments, anintercurrent illness is an acute illness—an illness with an abruptonset. An intercurrent illness can result in loss of physical functionor in muscle wasting, prolonged periods of time in bed, prolongedinflammation, infection, or prolonged physical therapy. An “injury” mayimpair the structure or function of the body and can result in loss ofphysical function or in muscle wasting, prolonged periods of time inbed, prolonged inflammation, infection, prolonged physical therapy, orrecovery from a surgical or invasive procedure. Injury includes, but isnot limited to, wounds, fractures, and burns. A “surgical procedure” or“other invasive procedure” may refer to a procedure that is carried outby entering the body through the skin or through a body cavity oranatomical opening, and includes procedures carried out in an operatingroom, surgical suite or procedure room. A “surgical procedure” caninclude, but is not limited to, heart surgery, knee replacement, hipreplacement, abdominal surgery, pelvic surgery, vascular surgery, spinesurgery, or an emergency procedure due to injury. An “invasiveprocedure” may include, but is not limited to, a colonoscopy,angioplasty, stent placement, endovascular coil placement, endovascularaneurysm repair, endoscopy, laparoscopy, arthroscopy, coronarycatheterization, or another cathether-based procedure. As notedpreviously, increased serum testosterone levels can be beneficial insuch subjects because testosterone has an anabolic effect, helping torebuild tissues, increase weight and muscle mass, and promote growth andmineralization of bone, thus may help in counteracting the deliteriousimpact of the surgical procedure, intercurrent illness, injury, etc.discussed above. “Restored sexual function” or “recovery of sexualfunction” may refer to an improvement in sexual function observed as sexhormone levels increase after suspension of once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof. For example, when serum testosterone levels arenormalized to above medical castration levels of >50 ng/dL becauseonce-daily administration of oral formulations comprising Compound 1, ora pharmaceutically acceptable salt thereof, is suspended, sexualfunction is improved. Sexual function and libido will continue toimprove as serum testosterone levels increase to above 50 ng/dL andreturn to normal (pre-treatment) levels. Improvement of sexual functionmay include, but is not limited to, improvements in libido, erectiledysfunction, arousal, orgasm, nocturnal erections, sexual desire, penilemorphology, ejaculation, quality of life, overall self-esteem, andoverall relationships.

Once-daily administration may also be suspended to improve the subject'squality of life and energy levels; to help with healing after injury,intercurrent illness, surgery, or radiation therapy; to aid subjects inremaining in control of their lifestyles, including an improvement insexual function; and to assist in regaining strength and mobility afterintercurrent illness or injury. Once administration is suspended, it mayor may not resume as needed. In some embodiments, once-dailyadministration resumes after the subject is recovered from anintercurrent illness, is no longer bedridden, has resumed normalactivities of daily living, or has regained a normal level of function(e.g., returns to the level of function the subject experience prior tothe illness).

The present disclosure provides for suspension of the once-dailyadministration of oral formulations of the disclosure prior to asurgical procedure or other invasive procedure or radiation therapy. Insome embodiments, once-daily administration may be suspended prior to asurgical procedure or other invasive procedure. In some embodiments,once-daily administration of oral formulations of the disclosure may besuspended after a surgical procedure or other invasive procedure,injury, or radiation therapy. In certain embodiments, once-dailyadministration of oral formulations of the disclosure occurs prior toand during the surgical procedure or other invasive procedure orradiation therapy and once-daily administration may be suspended afterthe surgical procedure or other invasive procedure or radiation therapy.In some embodiments, once-daily administration of oral formulations ofthe disclosure may be suspended during a surgical procedure or otherinvasive procedure, injury, or radiation therapy. In certainembodiments, once-daily administration of the oral formulations of thedisclosure may be suspended because the subject is in need of anincrease in serum testosterone levels due to a surgical procedure orother invasive procedure with a projected full recovery time of at leastabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24weeks, about 36 weeks, about 48 weeks, or about 52 weeks. In certainsuch embodiments, the recovery time is about 2 weeks. In someembodiments, once-daily administration of oral formulations of thedisclosure is not resumed after a suspension of administration prior to,after, or during a surgical procedure or other invasive procedure. Incertain such embodiments, once-daily administration is not resumed aftera suspension of administration after a surgical procedure or otherinvasive procedure. In some embodiments, the surgical procedure is heartsurgery, knee replacement, hip replacement, abdominal surgery, pelvicsurgery, vascular surgery, spine surgery, or an emergency procedure dueto injury. In certain embodiments of the methods and uses describedherein, the subject receiving prostate cancer treatment is identified asat risk for acute postoperative frailty.

The present disclosure provides for suspension of once-dailyadministration of oral formulations of the disclosure prior to radiationtherapy. In some embodiments, once-daily administration of oralformulations of the disclosure may be suspended after radiation therapy.Suspension of once-daily administration of oral formulations of thedisclosure after radiation therapy may aid in recovery from theradiation therapy yet permit therapeutic treatment with oralformulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, during radiation therapy, enabling intensive treatment ofprostate cancer. In certain embodiments, once-daily administration oforal formulations of the disclosure occurs prior to and during radiationtherapy and administration may be suspended after radiation therapy. Insome embodiments, once-daily administration of oral formulations of thedisclosure may be suspended during radiation therapy. In certainembodiments, once-daily administration of the oral formulations of thedisclosure may be suspended because the subject is in need of anincrease in serum testosterone levels due to radiation therapy for atleast about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24weeks, about 36 weeks, about 48 weeks, or about 52 weeks. In someembodiments, once-daily administration of oral formulations of thedisclosure is not resumed after a suspension of administration prior to,after, or during radiation therapy. In certain such embodiments,once-daily administration is not resumed after a suspension ofadministration after radiation therapy. In some embodiments, once-dailyadministration may be resumed when there is rise in PSA of “nadir+2ng/mL” after radiation therapy. In some embodiments, once-dailyadministration may be resumed after radiation therapy when the subject'sPSA level rises to ≥3 ng/mL, ≥10 ng/mL, ≥20 ng/mL, or ≥30 ng/mL.

In some embodiments, once-daily administration may be suspended duringan intercurrent illness or while the subject is bedridden. In someembodiments, once-daily administration may be suspended after anintercurrent illness. In certain embodiments, once-daily administrationof the oral formulations of the disclosure may be suspended because thesubject is in need of an increase in serum testosterone levels due to anintercurrent illness with a projected full recovery time of at leastabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24weeks, about 36 weeks, about 48 weeks, or about 52 weeks. In certainsuch embodiments, the recovery time is about 2 weeks. In someembodiments, once-daily administration of oral formulations of thedisclosure is not resumed after a suspension of administration after orduring an intercurrent illness. In certain such embodiments, once-dailyadministration is not resumed after a suspension of administration afteran intercurrent illness. In some embodiments, once-daily administrationof oral formulations of the disclosure may be suspended for anintercurrent illness, wherein the illness is stroke or cerebralhemorrhage. In certain embodiments, once-daily administration may besuspended for an intercurrent illness, wherein the illness is myocardialinfarction or congestive heart failure. In some embodiments, once-dailyadministration is suspended following an accident or injury requiringprolonged recovery. In some embodiments, once-daily administration issuspended following a stroke, cerebral hemorrhage, myocardialinfarction, congestive heart failure, hip fracture or other eventresulting in limited mobility and requiring prolonged recovery.

In certain embodiments, once-daily administration of the oralformulations of the disclosure may be suspended because the subject isin need of an increase in serum testosterone levels due to an injurywith a projected full recovery time of at least about 1 week, about 2weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks,about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48weeks, or about 52 weeks. In certain such embodiments, the recovery timeis about 2 weeks. In some embodiments, once-daily administration of oralformulations of the disclosure may be suspended for an injury, whereinthe injury is a bone fracture. In certain embodiments, once-dailyadministration may be suspended for an injury, wherein the injury is ahip fracture. In some embodiments, once-daily administration of oralformulations of the disclosure may be suspended for an injury, whereinthe injury is a knee injury.

The formulations of this disclosure may allow for a rise of serumtestosterone when medically needed. Stopping once-daily administrationof the oral formulations of the disclosure comprising Compound 1, or apharmaceutically acceptable salt thereof, may decrease the cataboliceffect of intercurrent/acute illness and bedrest in men with prostatecancer, thereby allowing for serum testosterone levels to rise to assistin regaining strength and mobility after an intercurrent/acute illness.This benefit cannot be achieved with the depot GnRH agonist/antagonistformulations. This intermittent androgen deprivation therapy mayminimize adverse events associated with continuous androgen deprivationtherapy while providing comparable efficacy for patients with prostatecancer.

The duration of the suspension period should be such that there isminimal adverse effect on the treatment due to the temporary stoppage ofonce-daily administration of oral formulations of the disclosure. Insome embodiments, the suspension period is from 4 weeks or less to 12weeks or greater. Longer suspension periods may be possible as long asthe subject's PSA levels remain low, such as <4 ng/mL or <0.2 ng/mL. Insome embodiments, once-daily administration may be resumed when there isrise in PSA of “nadir+2 ng/mL” during the suspension period. In someembodiments, once-daily administration may be resumed when the subject'sPSA level rises to ≥3 ng/mL, ≥10 ng/mL, ≥20 ng/mL, or ≥30 ng/mL duringthe suspension period. In some embodiments, the suspension period may beup to 60 weeks. In some embodiments, the suspension period may be up to52 weeks. In some embodiments, the suspension period may be up to 48weeks. In some embodiments, the suspension period may be up to 36 weeks.In some embodiments, the suspension period may be up to 24 weeks. Insome embodiments, the suspension period may be up to 20 weeks. In someembodiments, the suspension period may be up to 16 weeks. In someembodiments, the suspension period may be up to 12 weeks. In someembodiments, the suspension period may be up to 4 weeks. In someembodiments, the suspension period may be up to 8 weeks.

Depending on one or more of the following: symptom severity, subjectage, weight and sensitivity, the duration of the suspension period canbe altered. In some embodiments, as long as the PSA level is <4 ng/mL or<0.2 ng/mL, the subject may be off therapy. In some embodiments, thesuspension period is discontinued when the subject's prostate-specificantigen (PSA) level is ≥20% of the subject's PSA level of the nadirduring treatment. In some embodiments, the suspension period isdiscontinued when the subject's PSA level is ≥50% of the subject's PSAlevel prior to treatment. In certain embodiments, the suspension periodis discontinued when the subject's PSA level is greater than thesubject's PSA level at the beginning of the suspension period. In someembodiments, the suspension period is discontinued when the subjectexperiences return of symptoms of prostate cancer. In certainembodiments, the suspension period is discontinued when the subject'sPSA level is ≥3 ng/mL. In other embodiments, the suspension period isdiscontinued when the subject's PSA level is ≥10 ng/mL. In someembodiments, the suspension period is discontinued when the subject'sPSA level is ≥20 ng/mL. In other embodiments, the suspension period isdiscontinued when the subject's PSA level is ≥30 ng/mL.

In some embodiments, the time as to when a suspension period during thetreatment period can be taken by a subject should be such that there isa minimal adverse effect on the treatment due to the suspension period.In some embodiments, before a suspension period can be taken, a subjectmust have completed at least 4 consecutive weeks, at least 8 consecutiveweeks, at least 12 consecutive weeks, at least 16 consecutive weeks, atleast 20 consecutive weeks, at least 24 consecutive weeks, at least 36consecutive weeks, at least 48 consecutive weeks, at least 52consecutive weeks, at least 72 consecutive weeks, or at least 96consecutive weeks of treatment. In some embodiments, before a suspensionperiod can be taken, a subject must have completed at least 24consecutive weeks of treatment. In some embodiments, before a suspensionperiod can be taken, a subject must have completed at least 48consecutive weeks of treatment. As with duration, depending on one ormore of the following: symptom severity, subject age, weight andsensitivity, the time for taking the suspension period during thetreatment period can be altered.

With respect to onset, within about 4 to about 8 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure, the serum testosterone levels in the subject may be ator below medical castration level. In some embodiments, within 4 days offirst administering once-daily an oral formulation of the disclosure oran oral load dose formulation and an oral maintenance dose formulationof the disclosure, the serum testosterone levels in the subject may beat or below medical castration level. In some embodiments, within 5 daysof first administering once-daily an oral formulation of the disclosureor an oral load dose formulation and an oral maintenance doseformulation of the disclosure, the serum testosterone levels in thesubject may be at or below medical castration level. In someembodiments, within 6 days of first administering once-daily an oralformulation of the disclosure or an oral load dose formulation and anoral maintenance dose formulation of the disclosure, the serumtestosterone levels in the subject may be at or below medical castrationlevel. In some embodiments, within 7 days of first administeringonce-daily an oral formulation of the disclosure or an oral load doseformulation and an oral maintenance dose formulation of the disclosure,the serum testosterone levels in the subject may be at or below medicalcastration level. In some embodiments, within 8 days of firstadministering once-daily an oral formulation of the disclosure or anoral load dose formulation and an oral maintenance dose formulation ofthe disclosure, the serum testosterone levels in the subject may be ator below medical castration level. In some embodiments, within 3 days offirst administering once-daily an oral formulation of the disclosure oran oral load dose formulation and an oral maintenance dose formulationof the disclosure, the serum testosterone levels in the subject may beat or below medical castration level.

With further respect to onset, in some embodiments, followingadministration of an oral load dose formulation of the disclosureonce-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurestarting on the day after administering the last dose of the oral loaddose formulation, and continuing for a set treatment period (e.g., atleast 4 consecutive weeks or greater, at least 8 consecutive weeks orgreater, at least 12 consecutive weeks or greater, at least 16consecutive weeks or greater, at least 20 consecutive weeks or greater,24 consecutive weeks or greater, 36 consecutive weeks or greater, 48consecutive weeks or greater, 52 consecutive weeks or greater, 72consecutive weeks or greater, or 96 consecutive weeks or greater),medical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone may be achieved within 24 to 48 hours aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 6 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 1 week aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 2 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 weeks aftercommencing administration and maintained until the end ofadministration.

With further respect to onset, as described herein, following once-dailyadministration of an oral formulation comprising about 180 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, medical castration levels of less than or equal to 50ng/dL (1.73 nmol/L) serum testosterone may be achieved within 24 to 48hours after commencing administration. In some embodiments, followingonce-daily administration of an oral formulation of the disclosurecomprising about 180 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, serum testosterone levels in asubject may be at or below medical castration level within 3 days aftercommencing administration. In some embodiments, following once-dailyadministration of an oral formulation of the disclosure comprising about180 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, serum testosterone levels in a subject may beat or below medical castration level within 4 days after commencingadministration. In some embodiments, following once-daily administrationof an oral formulation of the disclosure comprising about 180 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, serum testosterone levels in a subject may be at or belowmedical castration level within 5 days after commencing administration.In some embodiments, following once-daily administration of an oralformulation of the disclosure comprising about 180 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 6 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 180 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 1 week after commencing administration.

With further respect to onset, as described herein, following once-dailyadministration of an oral formulation comprising about 80 mg to about160 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, medical castration levels of less than or equalto 50 ng/dL (1.73 nmol/L) serum testosterone may be achieved within 24to 48 hours after commencing administration. In some embodiments,following once-daily administration of an oral formulation of thedisclosure comprising about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 3 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 80 mg to about 160 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 4 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 80 mg to about 160 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 5 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 80 mg to about 160 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 6 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 80 mg to about 160 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 1 week after commencing administration.

With further respect to onset, as described herein, following once-dailyadministration of an oral formulation comprising about 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, medical castration levels of less than or equal to 50ng/dL (1.73 nmol/L) serum testosterone may be achieved within 24 to 48hours after commencing administration. In some embodiments, followingonce-daily administration of an oral formulation of the disclosurecomprising about 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, serum testosterone levels in asubject may be at or below medical castration level within 3 days aftercommencing administration. In some embodiments, following once-dailyadministration of an oral formulation of the disclosure comprising about120 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, serum testosterone levels in a subject may beat or below medical castration level within 4 days after commencingadministration. In some embodiments, following once-daily administrationof an oral formulation of the disclosure comprising about 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, serum testosterone levels in a subject may be at or belowmedical castration level within 5 days after commencing administration.In some embodiments, following once-daily administration of an oralformulation of the disclosure comprising about 120 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 6 days after commencing administration. In someembodiments, following once-daily administration of an oral formulationof the disclosure comprising about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,serum testosterone levels in a subject may be at or below medicalcastration level within 1 week after commencing administration.

With further respect to onset, in some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod (e.g., at least 4 consecutive weeks or greater, at least 8consecutive weeks or greater, at least 12 consecutive weeks or greater,at least 16 consecutive weeks or greater, at least 20 consecutive weeksor greater, 24 consecutive weeks or greater, 36 consecutive weeks orgreater, 48 consecutive weeks or greater, 52 consecutive weeks orgreater, 72 consecutive weeks or greater, or 96 consecutive weeks orgreater), medical castration levels of less than or equal to 50 ng/dL(1.73 nmol/L) serum testosterone may be achieved within 24 to 48 hoursafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 6 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 1 week aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 2 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 weeks aftercommencing administration and maintained until the end ofadministration.

With further respect to onset, in some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod (e.g., at least 4 consecutive weeks or greater, at least 8consecutive weeks or greater, at least 12 consecutive weeks or greater,at least 16 consecutive weeks or greater, at least 20 consecutive weeksor greater, 24 consecutive weeks or greater, 36 consecutive weeks orgreater, 48 consecutive weeks or greater, 52 consecutive weeks orgreater, 72 consecutive weeks or greater, or 96 consecutive weeks orgreater), medical castration levels of less than or equal to 50 ng/dL(1.73 nmol/L) serum testosterone may be achieved within 24 to 48 hoursafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 6 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 1 week aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 2 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 3 weeks aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below medical castration level within 4 weeks aftercommencing administration and maintained until the end ofadministration.

With further respect to onset, in some embodiments, followingadministration of an oral load dose formulation of the disclosurecomprising 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, once-daily for 1-3 days at thebeginning of treatment, and once-daily administration of an oralmaintenance dose formulation of the disclosure comprising 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod (e.g., at least 4 consecutive weeks or greater, at least 8consecutive weeks or greater, at least 12 consecutive weeks or greater,at least 16 consecutive weeks or greater, at least 20 consecutive weeksor greater, 24 consecutive weeks or greater, 36 consecutive weeks orgreater, 48 consecutive weeks or greater, 52 consecutive weeks orgreater, 72 consecutive weeks or greater, or 96 consecutive weeks orgreater), profound castration levels of less than or equal to 20 ng/dL(1.73 nmol/L) serum testosterone may be achieved within 24 to 48 hoursafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 3 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 4 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 5 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 6 days aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 1 week aftercommencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 2 weeksafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 3 weeksafter commencing administration and maintained until the end ofadministration. In some embodiments, following administration of an oralload dose formulation of the disclosure comprising 360 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof,once-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurecomprising 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, starting on the day afteradministering the last dose of the oral load dose formulation, andcontinuing for a set treatment period, serum testosterone levels in asubject may be at or below profound castration level within 4 weeksafter commencing administration and maintained until the end ofadministration.

In some embodiments of the methods and uses described herein, PSA may besuppressed in the subject to a level less than or equal to 4 ng/mL orless than or equal to 2 ng/mL.

During a treatment period (e.g., at least 4 consecutive weeks orgreater, at least 8 consecutive weeks or greater, at least 12consecutive weeks or greater, at least 16 consecutive weeks or greater,at least 20 consecutive weeks or greater, 24 consecutive weeks orgreater, 36 consecutive weeks or greater, 48 consecutive weeks orgreater, 52 consecutive weeks or greater, 72 consecutive weeks orgreater, or 96 consecutive weeks or greater) of once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, median time fromadministration of the first oral formulation to PSA nadir may be lessthan 5 weeks, less than 6 weeks, less than 7, weeks, less than 8 weeks,less than 9 weeks, less than 10 weeks, less than 11 weeks, less than 12weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, lessthan 16 weeks, less than 17 weeks, less than 18 weeks, less than 19weeks, less than 20 weeks, less than 21 weeks, less than 22 weeks, lessthan 23 weeks, less than 24 weeks, or less than 25 weeks. In someembodiments, during a treatment period of once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, median time from administration of the firstoral formulation to PSA nadir may be about 5 weeks to about 10 weeks,about 5 weeks to about 15 weeks, about 5 weeks to about 20 weeks, about5 weeks to about 25 weeks, about 10 weeks to about 15 weeks, about 10weeks to about 20 weeks, about 10 weeks to about 25 weeks, or about 15weeks to about 20 weeks. In some embodiments, during a treatment periodof once-daily administration of oral formulations comprising Compound 1,or a pharmaceutically acceptable salt thereof, median time fromadministration of the first oral formulation to PSA nadir may be about10 weeks to about 20 weeks. In some embodiments, after once-dailyadministration of oral formulations of the disclosure for 4 weeks, serumPSA levels are reduced by greater than or equal to about 5%, greaterthan or equal to about 10%, greater than or equal to about 20%, greaterthan or equal to about 30%, greater than or equal to about 40%, greaterthan or equal to about 50%, greater than or equal to about 60%, greaterthan or equal to about 70%, greater than or equal to about 80%, orgreater than or equal to about 90% of the subject's serum PSA levelsprior to treatment commencing. In some embodiments, after once-dailyadministration of oral formulations of the disclosure for 4 weeks, serumPSA levels are reduced by greater than or equal to about 50% of thesubject's serum PSA levels prior to treatment commencing.

In some embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment, and once-daily administration of an oral maintenance doseformulation of the disclosure starting on the day after administeringthe last dose of the oral load dose formulation, and continuing for aset treatment period, median time from commencing treatment to PSA nadirmay be less than 5 weeks, less than 6 weeks, less than 7, weeks, lessthan 8 weeks, less than 9 weeks, less than 10 weeks, less than 11 weeks,less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, lessthan 19 weeks, less than 20 weeks, less than 21 weeks, less than 22weeks, less than 23 weeks, less than 24 weeks, or less than 25 weeks. Insome embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment, and once-daily administration of an oral maintenance doseformulation of the disclosure starting on the day after administeringthe last dose of the oral load dose formulation, and continuing for aset treatment period, median time from commencing treatment to PSA nadirmay be about 5 weeks to about 10 weeks, about 5 weeks to about 15 weeks,about 5 weeks to about 20 weeks, about 5 weeks to about 25 weeks, about10 weeks to about 15 weeks, about 10 weeks to about 20 weeks, about 10weeks to about 25 weeks, or about 15 weeks to about 20 weeks. In someembodiments, following administration of an oral load dose formulationof the disclosure once-daily for 1-3 days at the beginning of treatment,and once-daily administration of an oral maintenance dose formulation ofthe disclosure starting on the day after administering the last dose ofthe oral load dose formulation, and continuing for a set treatmentperiod, median time from commencing treatment to PSA nadir may be about10 weeks to about 20 weeks. In some embodiments, 4 weeks aftercommencing administration of an oral load dose formulation of thedisclosure once-daily for 1-3 days, and once-daily administration of anoral maintenance dose formulation of the disclosure starting on the dayafter administering the last dose of the oral load dose formulation,serum PSA levels are reduced by greater than or equal to about 5%,greater than or equal to about 10%, greater than or equal to about 20%,greater than or equal to about 30%, greater than or equal to about 40%,greater than or equal to about 50%, greater than or equal to about 60%,greater than or equal to about 70%, greater than or equal to about 80%,or greater than or equal to about 90% of the subject's serum PSA levelsprior to treatment commencing. In some embodiments, 4 weeks aftercommencing administration of an oral load dose formulation of thedisclosure once-daily for 1-3 days, and once-daily administration of anoral maintenance dose formulation of the disclosure starting on the dayafter administering the last dose of the oral load dose formulation,serum PSA levels are reduced by greater than or equal to about 50% ofthe subject's serum PSA levels prior to treatment commencing.

After once-daily administration of oral formulations comprising Compound1, or a pharmaceutically acceptable salt thereof, for 1 week, 4 weeks,12 weeks, 24 weeks, or 48 weeks, serum FSH levels may be less than orequal to about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about1.2 mIU/mL. In certain such embodiments, once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, may result in sustained suppression of serumFSH levels. Normal FSH levels in adult males are typically between 1.5to 12.4 mIU/mL, but are elevated in subjects with prostate cancer. Insome embodiments, after once-daily administration of oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,for 1 week, serum FSH levels may be less than or equal to about 7.2mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL. In someembodiments, once-daily administration of oral formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof, for 1 week, 4weeks, 12 weeks, 24 weeks, or 48 weeks, may suppress serum FSH levels bygreater than or equal to about 80% or about 90% of the subject's serumFSH levels prior to treatment commencing.

In some embodiments, following administration of an oral load doseformulation of the disclosure once-daily for 1-3 days at the beginningof treatment, and once-daily administration of an oral maintenance doseformulation of the disclosure starting on the day after administeringthe last dose of the oral load dose formulation, serum FSH levels may beless than or equal to about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4mIU/mL, or about 1.2 mIU/mL 1 week, 4 weeks, 12 weeks, 24 weeks, or 48weeks after commencing treatment. In certain such embodiments,once-daily administration of oral formulations comprising Compound 1, ora pharmaceutically acceptable salt thereof, may result in sustainedsuppression of serum FSH levels. In some embodiments, followingadministration of an oral load dose formulation of the disclosureonce-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurestarting on the day after administering the last dose of the oral loaddose formulation, serum FSH levels may be less than or equal to about7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL 1week after commencing treatment. In some embodiments, followingadministration of an oral load dose formulation of the disclosureonce-daily for 1-3 days at the beginning of treatment, and once-dailyadministration of an oral maintenance dose formulation of the disclosurestarting on the day after administering the last dose of the oral loaddose formulation, serum FSH levels may be suppressed by greater than orequal to about 80% or about 90% of the subject's serum FSH levels priorto treatment commencing 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeksafter commencing treatment.

The disclosure also provides oral formulations comprising about 80 mg toabout 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, for use in a method oftreating prostate cancer in a subject in need thereof.

The disclosure provides oral formulations comprising about 80 mg toabout 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, for use in a method fortreating prostate cancer in a subject in need thereof, the methodcomprising: administering the oral formulation to the subject oncedaily; suspending administration of the oral formulation for asuspension period to allow for an increase of serum testosterone levels;and resuming administering to the subject once daily the oralformulation at the end of the suspension period.

The disclosure also provides for use of Compound 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of prostate cancer. In certain suchembodiments, the prostate cancer is hormone dependent prostate cancer,advanced prostate cancer, metastatic, non-metastatic, locally advanced,advanced hormone sensitive, advanced castration resistant, recurrent,castration-resistant metastatic prostate cancer, castration-resistantnon-metastatic prostate cancer, hormone-sensitive metastatic prostatecancer, or hormone-sensitive non-metastatic prostate cancer. In someembodiments, the medicament comprises 80 mg to about 480 mg of Compound1, or a corresponding amount of the pharmaceutically acceptable saltthereof.

Methods and uses described herein may provide androgen deprivation inprostate cancer without increasing risk of hyperglycemia and diabetes ascompared to GnRH agonists (e.g., Lupron). Unlike other GnRH antagonists(e.g., degarelix), oral formulations of the disclosure provide androgendeprivation without need for injection.

Methods and uses described herein may delay progression of castrationresistant disease. In particular, Compound 1, or a pharmaceuticallyacceptable salt thereof, may offer improved disease control whencompared with a GnRH agonist in terms of superior FSH suppression andPSA progression-free survival.

Methods and uses described herein may be used to achieve theanti-androgen withdrawal syndrome. An “anti-androgen” may refer to anydrug or substance that decreases the levels or activity of androgens.Anti-androgens tend to inhibit the production, activity, or effects of amale sex hormone or prevent androgens like testosterone ordihydrotestosterone from mediating their biological effects in the body.The anti-androgen withdrawal syndrome is a well-established phenomenonin prostate cancer. It is widely accepted that a subset of patients willbenefit from the withdrawal of anti-androgen or steroidal hormone fromhormonal therapy, exhibiting decreasing PSA values and clinicalimprovement.

Methods and uses described herein may be employed to provide heartbenefits. The cardiac benefits may be linked to better FSH suppressioncompared to agonists. Methods and uses described herein may be employedto provide ADT with lower rates of cardiovascular side effects comparedto agonists. Also, the formulations of the present disclosure may beuseful in sexual reassignment/cross gender transition protocols.Further, the formulations of the present disclosure may be useful inpreserving fertility during chemotherapy.

Dosing and Administration

Although GnRH agonists and antagonists are typically given eithersubcutaneously, intramuscularly or intranasally, including by depotformulations, Compound 1, or a pharmaceutically acceptable salt thereof,may be administered orally and once-daily, making dose administrationeasier and more convenient.

For treatment of prostate cancer, Compound 1, or a pharmaceuticallyacceptable salt thereof, may be administered orally once-daily, andformulated with a pharmaceutically acceptable carrier or excipients. Insome embodiments, the dosage formulation is a solid preparation, such asa tablet, capsule, granule, or powder, for oral administration.

In some embodiments, the oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, have an immediate releaseprofile. However, the oral formulation may have other release profilesincluding, for example, sustained release, controlled release, delayedrelease and extended release.

In some embodiments, the periods of once-daily administration for oralformulations comprising Compound 1, or a pharmaceutically acceptablesalt thereof, in the methods and uses described herein are: at least 4consecutive weeks or greater, at least 8 consecutive weeks or greater,at least 12 consecutive weeks or greater, at least 16 consecutive weeksor greater, at least 20 consecutive weeks or greater, 24 consecutiveweeks or greater, 36 consecutive weeks or greater, 48 consecutive weeksor greater, 52 consecutive weeks or greater, 72 consecutive weeks orgreater, or 96 consecutive weeks or greater. In some embodiments, theperiods of once-daily administration are 4 consecutive weeks or greater.In some embodiments, the periods of once-daily administration are 8consecutive weeks or greater. In some embodiments, the periods ofonce-daily administration are 12 consecutive weeks or greater. In someembodiments, the periods of once-daily administration are 16 consecutiveweeks or greater. In some embodiments, the periods of once-dailyadministration are 20 consecutive weeks or greater. In some embodiments,the periods of once-daily administration are 24 consecutive weeks orgreater. In some embodiments, the periods of once-daily administrationare 36 consecutive weeks or greater. In some embodiments, the periods ofdaily administration are 48 consecutive weeks or greater. In someembodiments, the periods of once-daily administration are 52 consecutiveweeks or greater. In some embodiments, the periods of once-dailyadministration are 72 consecutive weeks or greater. In some embodiments,the periods of once-daily administration are 96 consecutive weeks orgreater.

The methods and uses described herein include chronic administration.For example, the treatment periods using oral formulations comprisingCompound 1, or a pharmaceutically acceptable salt thereof, for treatingprostate cancer in a subject and suppressing PSA and/or one or more sexhormones in a subject, including testosterone, LH, and FSH, may be of along duration, such as, once-daily administration for consecutive dayperiods of 48 weeks or greater, once-daily administration forconsecutive day periods of 52 consecutive weeks or greater, once-dailyadministration for consecutive day periods of 72 consecutive weeks orgreater, once-daily administration for consecutive day periods of 76weeks or greater, once-daily administration for consecutive day periodsof 96 weeks or greater, once-daily administration for consecutive dayperiods of 104 weeks or greater, or once-daily administration forconsecutive day periods of 128 weeks or greater. In certain suchembodiments, the treatment period is once-daily administration forconsecutive day periods of 48 weeks or greater.

The methods and uses described herein include administering, once-daily,oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof for the treatmentof prostate cancer. In certain such embodiments, the oral formulationcomprises at least about 80 mg to about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral formulation comprises about 80 mg, about 120mg, about 160 mg, about 180 mg, or about 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral formulation comprises about 80 mg to about160 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In certain embodiments, the oral formulationcomprises about 240 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral formulation comprises about 80 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof.In some embodiments, the oral formulation comprises about 120 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof. In some embodiments, the oral formulation comprises about160 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the oral formulationcomprises about 180 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralformulation comprises about 360 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral formulation comprises about 240 mg of Compound 1,or a corresponding amount of a pharmaceutically acceptable salt thereof.

The present disclosure provides once-daily administration of oralformulations such as an oral load dose formulation comprising Compound1, or a pharmaceutically acceptable salt thereof, and an oralmaintenance dose formulation comprising Compound 1, or apharmaceutically acceptable salt thereof, to a subject in need oftreatment for prostate cancer. In some embodiments, the oral load doseformulation is a tablet or capsule and the oral maintenance doseformulations are a tablet or capsule. In some embodiments, the oral loaddose formulation has an immediate release profile. However, the oralload dose formulation can have other release profiles including, forexample, sustained release, controlled release, delayed release andextended release. In some embodiments, the oral maintenance doseformulation has an immediate release profile. However, the oralmaintenance dose formulation can have other release profiles including,for example, sustained release, controlled release, delayed release andextended release. In some embodiments, both the oral load and oralmaintenance dose formulations are immediate release formulations.

In some embodiments, an oral load dose formulation comprising Compound1, or a pharmaceutically acceptable salt thereof, may be administeredonce-daily to begin treatment of prostate cancer and the duration ofadministration is between 1 and 3 days. In some embodiments, an oralload dose formulation comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, may be administered once-daily to begintreatment of prostate cancer and the duration of administration is 1day. In some embodiments, an oral load dose formulation comprisingCompound 1, or a pharmaceutically acceptable salt thereof, may beadministered once-daily to begin treatment of prostate cancer and theduration of administration is 2 days. In some embodiments, an oral loaddose formulation comprising Compound 1, or a pharmaceutically acceptablesalt thereof, may be administered once-daily to begin treatment ofprostate cancer and the duration of administration is 3 days.

Oral load dose formulations of the disclosure may comprise about 240 toabout 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, such as about 320 mg to about400 mg. In some embodiments, the oral load dose formulation of thedisclosure comprises about 240 mg, about 320 mg, about 360 mg, or about480 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the oral load doseformulation of the disclosure comprises about 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral load dose formulation of the disclosurecomprises about 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralload dose formulation of the disclosure comprises about 320 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof. In some embodiments, the oral load dose formulation of thedisclosure comprises about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

Thereafter, and sometimes combined during the duration of the oral loaddose formulation, there is once-daily administration of an oralmaintenance dose formulation. In some embodiments, the oral maintenancedose formulation once-daily administration begins on the day afteradministering the last dose of the oral load dose formulation. In someembodiments, the oral maintenance dose formulation of the disclosurecomprises about 80 mg to about 160 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, such as about 100mg to about 140 mg. In some embodiments, the oral maintenance doseformulation of the disclosure comprises about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral maintenance dose formulation of thedisclosure comprises about 160 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral maintenance dose formulation of the disclosurecomprises about 80 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralmaintenance dose formulation of the disclosure comprises about 180 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof.

In some embodiments, the oral load dose formulation of the disclosuremay be administered once-daily for 1-3 days at the beginning oftreatment and each dose comprises about 240 to about 480 mg of Compound1, or a corresponding amount of a pharmaceutically acceptable saltthereof, such as about 320 mg to about 400 mg. In some embodiments, theoral load dose formulation of the disclosure may be administeredonce-daily for 1-3 days at the beginning of treatment and each dosecomprises about 240 mg, about 320 mg, about 360 mg, or about 480 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof. In some embodiments, the oral load dose formulation of thedisclosure may be administered once-daily for 1-3 days at the beginningof treatment and each dose comprises about 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral load dose formulation of the disclosure maybe administered once-daily for 1-3 days at the beginning of treatmentand each dose comprises about 240 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 1-3 days at the beginning of treatment andeach dose comprises about 320 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 1-3 days at the beginning of treatment andeach dose comprises about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In some embodiments, the oral load dose formulation of the disclosuremay be administered once-daily for 1 day at the beginning of treatmentand each dose comprises about 240 to about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, suchas about 320 mg to about 400 mg. In some embodiments, the oral load doseformulation of the disclosure may be administered once-daily for 1 dayat the beginning of treatment and each dose comprises about 240 mg,about 320 mg, about 360 mg, or about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral load dose formulation of the disclosure maybe administered once-daily for 1 day at the beginning of treatment andeach dose comprises about 360 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 1 day at the beginning of treatment and eachdose comprises about 240 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof. In some embodiments, theoral load dose formulation of the disclosure may be administeredonce-daily for 1 day at the beginning of treatment and each dosecomprises about 320 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralload dose formulation of the disclosure may be administered once-dailyfor 1 day at the beginning of treatment and each dose comprises about480 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof.

In some embodiments, the oral load dose formulation of the disclosuremay be administered once-daily for 2 days at the beginning of treatmentand each dose comprises about 240 to about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, suchas about 320 mg to about 400 mg. In some embodiments, the oral load doseformulation of the disclosure may be administered once-daily for 2 daysat the beginning of treatment and each dose comprises about 240 mg,about 320 mg, about 360 mg, or about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral load dose formulation of the disclosure maybe administered once-daily for 2 days at the beginning of treatment andeach dose comprises about 360 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 2 days at the beginning of treatment andeach dose comprises about 240 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 2 days at the beginning of treatment andeach dose comprises about 320 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 2 days at the beginning of treatment andeach dose comprises about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In some embodiments, the oral load dose formulation of the disclosuremay be administered once-daily for 3 days at the beginning of treatmentand each dose comprises about 240 to about 480 mg of Compound 1, such asabout 320 mg to about 400 mg, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralload dose formulation of the disclosure may be administered once-dailyfor 3 days at the beginning of treatment and each dose comprises about240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, the oral load dose formulation of the disclosure maybe administered once-daily for 3 days at the beginning of treatment andeach dose comprises about 360 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 3 days at the beginning of treatment andeach dose comprises about 240 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 3 days at the beginning of treatment andeach dose comprises about 320 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral load dose formulation of the disclosure may beadministered once-daily for 3 days at the beginning of treatment andeach dose comprises about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

In some embodiments, an oral maintenance dose formulation of thedisclosure may be administered once-daily and comprises about 80 mg toabout 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, such as about 100 mg to about140 mg. In some embodiments, the oral maintenance dose formulation ofthe disclosure may be administered once-daily and comprises about 120 mgof Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the oral maintenance doseformulation of the disclosure may be administered once-daily andcomprises about 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralmaintenance dose formulation of the disclosure may be administeredonce-daily and comprises about 80 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral maintenance dose formulation of the disclosure maybe administered once-daily and comprises about 180 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the oral maintenance dose formulations of thedisclosure may be administered once-daily for 4 consecutive weeks orgreater, 8 consecutive weeks or greater, 12 consecutive weeks orgreater, 16 consecutive weeks or greater, 20 consecutive weeks orgreater, 24 consecutive weeks or greater, 36 consecutive weeks orgreater, 48 consecutive weeks or greater, 52 consecutive weeks orgreater, 72 consecutive weeks or greater, or 96 consecutive weeks orgreater. In some embodiments, the oral maintenance dose formulations ofthe disclosure may be administered once-daily for 4 consecutive weeks orgreater. In some embodiments, the oral maintenance dose formulations ofthe disclosure may be administered once-daily for 8 consecutive weeks orgreater. In some embodiments, the oral maintenance dose formulations ofthe disclosure may be administered once-daily for 12 consecutive weeksor greater. In some embodiments, the oral maintenance dose formulationsof the disclosure may be administered once-daily for 16 consecutiveweeks or greater. In some embodiments, the oral maintenance doseformulations of the disclosure may be administered once-daily for 20consecutive weeks or greater. In some embodiments, the oral maintenancedose formulations of the disclosure may be administered once-daily for24 consecutive weeks or greater. In some embodiments, the oralmaintenance dose formulations of the disclosure may be administeredonce-daily for 36 consecutive weeks or greater. In some embodiments, theoral maintenance dose formulations of the disclosure may be administeredonce-daily for 48 consecutive weeks or greater. In some embodiments, theoral maintenance dose formulations of the disclosure may be administeredonce-daily for 52 consecutive weeks or greater. In some embodiments, theoral maintenance dose formulations of the disclosure may be administeredonce-daily for 72 consecutive weeks or greater. In some embodiments, theoral maintenance dose formulations of the disclosure may be administeredonce-daily for 96 consecutive weeks or greater. For chronicadministration, the oral maintenance dose formulations of the disclosuremay be administered once-daily for: consecutive day periods of 48 weeksor greater, consecutive day periods of 52 consecutive weeks or greater,consecutive day periods of 72 consecutive weeks or greater, consecutiveday periods of 76 weeks or greater, consecutive day periods of 96 weeksor greater, consecutive day periods of 104 weeks or greater, orconsecutive day periods of 128 weeks or greater. In certain suchembodiments, the oral maintenance dose formulations of the disclosuremay be administered once-daily for consecutive day periods of 48 weeksor greater.

In some embodiments, the oral load dose formulation of the disclosurecomprises about 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and may be administered onceon day 1 of the treatment period, and the oral maintenance doseformulations of the disclosure comprise about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andmay be administered once-daily starting on day 2 of the treatmentperiod. In certain such embodiments, the daily oral maintenance doseformulations may be administered once-daily for a 12 consecutive weeksor greater treatment period. In some embodiments, the daily oralmaintenance dose formulations of the disclosure may be administeredonce-daily for a 48 consecutive weeks or greater treatment period.

In some embodiments, the oral load dose formulation of the disclosurecomprises about 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and may be administered onceon day 1 of the treatment period, and the oral maintenance doseformulations of the disclosure comprise about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andmay be administered once-daily starting on day 2 of the treatmentperiod. In certain such embodiments, the daily oral maintenance doseformulations may be administered once-daily for a 12 consecutive weeksor greater treatment period. In some embodiments, the daily oralmaintenance dose formulations of the disclosure may be administeredonce-daily for a 48 consecutive weeks or greater treatment period.

In some embodiments, the oral load dose formulation of the disclosurecomprises about 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and may be administered onceon day 1 of a first treatment period, and the oral maintenance doseformulations of the disclosure comprise about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andmay be administered once-daily starting on day 1 or day 2 of a secondtreatment period. In certain such embodiments, the daily oralmaintenance dose formulations may be administered once-daily for a 12consecutive weeks or greater treatment period. In some embodiments, thedaily oral maintenance dose formulations of the disclosure may beadministered once-daily for a 48 consecutive weeks or greater treatmentperiod.

In some embodiments, the oral load dose formulation of the disclosurecomprises about 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and may be administered onceon day 1 of a first treatment period, and the oral maintenance doseformulations of the disclosure comprise about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andmay be administered once-daily starting on day 1 or day 2 of a secondtreatment period. In certain such embodiments, the daily oralmaintenance dose formulations may be administered once-daily for a 12consecutive weeks or greater treatment period. In some embodiments, thedaily oral maintenance dose formulations of the disclosure may beadministered once-daily for a 48 consecutive weeks or greater treatmentperiod.

The present disclosure further provides that once-daily administrationof oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, can be suspended for a suspension period,thereby allowing for an increase in a subject's serum testosteronelevels. Increased serum testosterone levels during the suspension periodmay enable subjects to remain in control of their lifestyle and qualityof life (e.g., maintenance of sexual activity). In some embodiments, thesuspension occurs after the oral formulation of the disclosure isadministered once-daily for 4 consecutive weeks or greater. In someembodiments, the suspension occurs after the oral formulation of thedisclosure is administered once-daily for 8 consecutive weeks orgreater. In some embodiments, the suspension occurs after the oralformulation of the disclosure is administered once-daily for 12consecutive weeks or greater. In some embodiments, the suspension occursafter the oral formulation of the disclosure is administered once-dailyfor 16 consecutive weeks or greater. In some embodiments, the suspensionoccurs after the oral formulation of the disclosure is administeredonce-daily for 20 consecutive weeks or greater. In some embodiments, thesuspension occurs after the oral formulation of the disclosure isadministered once-daily for 24 consecutive weeks or greater. In someembodiments, the suspension occurs after the oral formulation of thedisclosure is administered once-daily for 36 consecutive weeks orgreater. In some embodiments, the suspension occurs after the oralformulation of the disclosure is administered once-daily for 48consecutive weeks or greater. In some embodiments, the suspension occursafter the oral formulation of the disclosure is administered once-dailyfor 52 consecutive weeks or greater. In some embodiments, the suspensionoccurs after the oral formulation of the disclosure is administeredonce-daily for 72 consecutive weeks or greater. In some embodiments, thesuspension occurs after the oral formulation of the disclosure isadministered once-daily for 96 consecutive weeks or greater. In someembodiments, the administration of the oral formulation of thedisclosure is suspended after at least 24 consecutive weeks ofonce-daily administration. In some embodiments, the administration ofthe oral formulation of the disclosure is suspended after at least 48consecutive weeks of once-daily administration.

The suspension period may last until the desired increase in a subject'sserum testosterone levels is achieved or may last as long as required.In some embodiments, the suspension period may last until the PSA beginsto rise. In some embodiments, once-daily administration may be resumedwhen there is rise in PSA of “nadir+2 ng/mL.” In some embodiments,once-daily administration may be resumed when the subject's PSA level is≥3 ng/mL, ≥10 ng/mL, ≥20 ng/mL, or ≥30 ng/mL. In some embodiments, thesuspension period may be up to 60 weeks. In some embodiments, thesuspension period may be up to 52 weeks. In some embodiments, thesuspension period may be up to 48 weeks. In some embodiments, thesuspension period may be up to 36 weeks. In some embodiments, thesuspension period may be up to 24 weeks. In some embodiments, thesuspension period may be up to 20 weeks. In some embodiments, thesuspension period may be up to 16 weeks. In some embodiments, thesuspension period may be up to 12 weeks. In some embodiments, thesuspension period may be up to 4 weeks. In some embodiments, thesuspension period may be up to 8 weeks.

In some embodiments, the once-daily administration of oral formulationsof the disclosure comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, for all methods and uses disclosed herein canbe suspended for a period of 4 weeks or less, after at least 24consecutive weeks of once-daily administration. In some embodiments, theonce-daily administration of oral formulations of the disclosurecomprising Compound 1, or a pharmaceutically acceptable salt thereof,for all methods and uses disclosed herein can be suspended for a periodof 4 weeks or less to 8 weeks or greater, after at least 24 consecutiveweeks of once-daily administration. In some embodiments, the once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, for all methods and usesdisclosed herein can be suspended for a period of 4 weeks or less to 12weeks or greater, after at least 24 consecutive weeks of once-dailyadministration. In some embodiments, the once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, for all methods and uses disclosed herein canbe suspended for a period of 4 weeks or less to 16 weeks or greater,after at least 24 consecutive weeks of once-daily administration. Insome embodiments, the once-daily administration of oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,for all methods and uses disclosed herein can be suspended for a periodof 4 weeks or less to 20 weeks or greater, after at least 24 consecutiveweeks of once-daily administration. In some embodiments, the once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, for all methods and usesdisclosed herein can be suspended for a period of 4 weeks or less to 24weeks or greater, after at least 24 consecutive weeks of once-dailyadministration. In some embodiments, the once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, for all methods and uses disclosed herein canbe suspended for a period of 4 weeks or less to 36 weeks or greater,after at least 24 consecutive weeks of once-daily administration. Insome embodiments, the once-daily administration of oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,for all methods and uses disclosed herein can be suspended for a periodof 4 weeks or less to 48 weeks or greater, after at least 24 consecutiveweeks of once-daily administration. In some embodiments, the once-dailyadministration of oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, for all methods and usesdisclosed herein can be suspended for a period of 4 weeks or less to 52weeks or greater, after at least 24 consecutive weeks of once-dailyadministration. In some embodiments, the once-daily administration oforal formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, for all methods and uses disclosed herein canbe suspended for a period of 4 weeks or less to 60 weeks or greater,after at least 24 consecutive weeks of once-daily administration.

The present disclosure provides for resumption of once-dailyadministration of oral formulations of the disclosure following asuspension period. In some embodiments, once-daily administration oforal formulations of the disclosure comprising about 80 mg to about 480mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, is resumed at the end of the suspension period.

The present disclosure also provides for once-daily administration oforal load dose formulations after a suspension period. In someembodiments, an oral load dose formulation of the disclosure comprisingabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, may be administeredonce-daily for 1-3 days at the beginning of the treatment period afterthe suspension period. In some embodiments, the oral load doseformulation of the disclosure may be administered once-daily for 1 dayafter the suspension period. In some embodiments, the oral load doseformulation of the disclosure may be administered once-daily for 2 daysafter the suspension period. In some embodiments, the oral load doseformulation of the disclosure may be administered once-daily for 3 daysafter the suspension period.

After a suspension period, the present disclosure provides foradministration of a once-daily oral maintenance dose formulation of thedisclosure comprising about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof,beginning after administering the last dose of the oral load doseformulation of the disclosure. In some embodiments following asuspension period, administration of the once-daily oral maintenancedose formulation of the disclosure comprising about 80 mg to about 160mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, begins on the day after administering the lastdose of the oral load dose formulation of the disclosure.

In certain embodiments with intermittent dosing involving separatetreatment periods, the oral load dose formulation of the disclosure maybe administered once-daily for 1-3 days at the beginning of eachtreatment period. In certain embodiments with intermittent dosinginvolving separate treatment periods, the oral maintenance doseformulation of the disclosure may be administered once-daily at thebeginning of each treatment period.

After resuming administration of oral formulations or oral maintenancedose formulations of the disclosure following a suspension period, theoral formulations or oral maintenance dose formulations may beadministered once-daily for 4 consecutive weeks or greater, 8consecutive weeks or greater, 12 consecutive weeks or greater, 16consecutive weeks or later, 20 consecutive weeks or greater, 24consecutive weeks or greater, 36 consecutive weeks or greater, 48consecutive weeks or greater, 52 consecutive weeks or greater, 72consecutive weeks or greater, or 96 consecutive weeks or greater. Insome embodiments, the oral formulations or oral maintenance doseformulations of the disclosure may be administered once-daily for 4consecutive weeks or greater following a suspension period. In someembodiments, the oral formulations or oral maintenance dose formulationsof the disclosure may be administered once-daily for 8 consecutive weeksor greater following a suspension period. In some embodiments, the oralformulations or oral maintenance dose formulations of the disclosure maybe administered once-daily for 12 consecutive weeks or greater followinga suspension period. In some embodiments, the oral formulations or oralmaintenance dose formulations of the disclosure may be administeredonce-daily for 16 consecutive weeks or greater following a suspensionperiod. In some embodiments, the oral formulations or oral maintenancedose formulations of the disclosure may be administered once-daily for20 consecutive weeks or greater following a suspension period. In someembodiments, the oral formulations or oral maintenance dose formulationsof the disclosure may be administered once-daily for 24 consecutiveweeks or greater following a suspension period. In some embodiments, theoral formulations or oral maintenance dose formulations of thedisclosure may be administered once-daily for 36 consecutive weeks orgreater following a suspension period. In some embodiments, the oralformulations or oral maintenance dose formulations of the disclosure maybe administered once-daily for 48 consecutive weeks or greater followinga suspension period. In some embodiments, the oral formulations or oralmaintenance dose formulations of the disclosure may be administeredonce-daily for 52 consecutive weeks or greater following a suspensionperiod. In some embodiments, the oral formulations or oral maintenancedose formulations of the disclosure may be administered once-daily for72 consecutive weeks or greater following a suspension period. In someembodiments, the oral formulations or oral maintenance dose formulationsof the disclosure may be administered once-daily for 96 consecutiveweeks or greater following a suspension period. For chronicadministration after a suspension period, the oral formulations or oralmaintenance dose formulations of the disclosure may be administeredonce-daily for: consecutive day periods of 48 weeks or greater,consecutive day periods of 52 consecutive weeks or greater, consecutiveday periods of 72 consecutive weeks or greater, consecutive day periodsof 76 weeks or greater, consecutive day periods of 96 weeks or greater,consecutive day periods of 104 weeks or greater, or consecutive dayperiods of 128 weeks or greater. In certain such embodiments, the oralformulations or oral maintenance dose formulations of the disclosure maybe administered once-daily for consecutive day periods of 48 weeks orgreater.

In some embodiments, the once-daily administration of oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof, issuspended for a subsequent suspension period after completion of aninitial suspension period and resumption of administration. In certainsuch embodiments, the subsequent suspension period occurs at least 12weeks after resuming once-daily administration of an oral formulationcomprising about 80 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof.

The present disclosure also provides for not resuming administrationonce it is suspended. For example, in some embodiments, administrationmay be suspended after radiation therapy is completed and not resumed.In some embodiments, administration after radiation therapy is completedwill not be resumed until the PSA rises. In some embodiments, once-dailyadministration may be resumed when there is rise in PSA of “nadir+2ng/mL” after radiation therapy. In some embodiments, once-dailyadministration may resumed after radiation therapy when the subject'sPSA level is ≥3 ng/mL, ≥10 ng/mL, ≥20 ng/mL, or ≥30 ng/mL.

In some embodiments, administration of the oral formulations of thepresent disclosure is food dependent. In certain such embodiments,administration is preferably before any meal. In some embodiments, theoral formulation comprising Compound 1, or a pharmaceutically acceptablesalt thereof, may be administered pre-prandial. In some embodiments,administration is at least 1 hour before eating or at least 2 hoursafter eating. In other embodiments, administration can also be at least30 minutes before eating or while the subject is fasting. In someembodiments, administration is about 2 hours before eating or 1 hourafter eating. In some embodiments, administration is at least 30 minutesbefore eating, 1 hour before eating, or 2 hours before eating. In someembodiments, administration is at least 30 minutes after eating, 1 hourafter eating, or 2 hours after eating.

In some embodiments, the administration of the oral formulations of thedisclosure is without any fasting or eating schedule requirement. Insome embodiments, the administration is without any fasting requirement.In certain such embodiments, the administration of the oral formulationcan be food independent. In some embodiments, administration can beduring a meal.

The present disclosure provides that the administration for all methodsand uses described herein is such that there is no stimulation of sexhormones, and thereby flare is prevented or minimized in subjects.

Depending on one or more of the following: symptom severity, subjectage, weight and sensitivity, and risk factors, such as whether a smoker,and existing medications, the duration and intervals of administrationcan be altered.

Dosage Forms of the Disclosure

As used herein, the oral formulations of the disclosure may include, butare not limited to, tablets, capsules, caplets, pills, oral dissolvingfilms, lozenges, gums, granules, and powders. In some embodiments, theoral formulation is a tablet or a capsule.

In some embodiments, the oral formulations, including the oral load andmaintenance dose formulations, disclosed herein have an immediaterelease profile. However, the oral formulations can have other releaseprofiles including, for example, sustained release, controlled release,delayed release and extended release. In some embodiments, the oralformulations disclosed herein have a sustained release profile. In someembodiments, the oral formulations disclosed herein have controlledrelease profile. In some embodiments, the oral formulations disclosedherein have a delayed release profile. In some embodiments, the oralformulations disclosed herein have an extended release profile.

The excipients of the oral formulations of the disclosure are a blend ofexcipients, and amounts, that help to optimize the efficacy of theformulation. The following are core excipients and include variousorganic or inorganic excipients or carrier substances, including, butnot limited to, one or more fillers or diluents, lubricants, binders,surfactants, pH adjusters, sweeteners, flavors, and disintegrants. Therecan be a film coat with pharmaceutical additives, including, but notlimited to, one or more film formers, coating bases, coating additives,plasticizers, organic acids, pigments or antioxidants, light shieldingagents, flow-aids or polishing agents, and colorants.

Diluents or fillers for use in the present disclosure include organicmaterials and inorganic materials including, but not limited to,dextrose, lactose, mannitol, D-mannitol (e.g., PEARLITOL 50C, PEARLITOL100SD, PEARLITOL 200SD, PEARLITOL 300 DC, and PEARLITOL 400DC), sodiumstarch, sucrose, calcium phosphate, anhydrous calcium phosphate,precipitated calcium carbonate, calcium sulfate, calcium carbonate,calcium silicate, sorbitol, corn starch, potato starch, wheat starch,rice starch, partly pregelatinized starch, pregelatinized starch, porousstarch, and calcium carbonate starch. In some embodiments, the diluentis mannitol. Diluents or fillers for use in the present disclosureinclude organic materials and inorganic materials also include, but arenot limited to, hydroxypropyl cellulose, crystalline cellulose (e.g.,CEOLUS KG-802 (grade: KG-802) and CEOLUS PH-302 (grade: PH-302)),crystalline cellulose (particles), crystalline cellulose (fineparticles), microcrystalline cellulose, hydroxypropyl methylcellulose(e.g., hypromellose 2910), starch, gelatin, sucrose, dextrin, lactose,povidone (polyvinylpyrrolidone), copolyvidone, acacia, sodium alginate,and carboxymethylcellulose. In some embodiments, the diluent isD-mannitol. In some embodiments, the diluent is microcrystallinecellulose. In some embodiments, the diluent is lactose.

Binders for use in the present disclosure include, but are not limitedto, hydroxypropyl cellulose, crystalline cellulose (e.g., CEOLUS KG-802(grade: KG-802) and CEOLUS PH-302 (grade: PH-302)), crystallinecellulose (particles), crystalline cellulose (fine particles),microcrystalline cellulose, hydroxypropyl methylcellulose (e.g.,hypromellose 2910), starch, gelatin, sucrose, dextrin, lactose, povidone(polyvinylpyrrolidone), and copolyvidone. Natural and synthetic gumsthat can be used as binders include, but are not limited to, acacia,sodium alginate, and carboxymethylcellulose. In some embodiments, thebinder is hydroxypropyl methylcellulose. In some embodiments, the binderis hydroxypropyl cellulose.

Disintegrants for use in the present disclosure include, but are notlimited to, crosslinked polymers, such as crosslinkedpolyvinylpyrrolidone (crospovidone), crosslinked sodium carboxylmethylcellulose (croscarmellose sodium), crosslinked carmellose sodium,microcrystalline cellulose, carboxymethyl cellulose, carboxylmethylcellulose calcium, carboxylmethyl starch sodium, and sodium starchglycolate. Additional disintegrants for use in the present disclosureinclude, but are not limited to, corn starch, sodium carboxymethylstarch, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylstarch, and magnesium alumino metasilicate. In some embodiments, thedisintegrant is sodium starch glycolate. In some embodiments, thedisintegrant is crosslinked sodium carboxylmethyl cellulose.

Lubricants for use in the present disclosure include, but are notlimited to, magnesium stearate; stearic acid; sodium stearyl fumarate;triethyl citrate; inorganic lubricants, namely talc, colloidal silicaand fumed silicon dioxide; polymeric lubricants, such as polyethyleneglycol, PEG 4000, and PEG 6000; mineral oils; and hydrogenated vegetableoils. However, other compounds, such as fatty acids and metallic saltsthereof, fatty acid esters and salts thereof, organic waxes, polymersand inorganic substances, can be employed. Useful fatty acids include,but are not limited to, lauric acid, palmitic acid and stearic acid.Useful metallic salts include, but are not limited to, those of calcium,magnesium and zinc. Useful fatty acid esters include, but are notlimited to, glyceride esters, such as glyceryl monostearate, glyceryltribehenate, glyceryl palmitostearate and glyceryl dibehenate. Usefulsugar esters include, but are not limited to, sucrose esters of fattyacids, sorbitan monostearate, and sucrose monopalmitate. Useful saltsthereof include, but are not limited to, sodium oleate, sodium benzoate,sodium acetate, magnesium lauryl sulfate, and sodium lauryl sulfate. Insome embodiments, lubricants include magnesium stearate, calciumstearate, talc, and colloidal silica. In some embodiments, the lubricantis magnesium stearate. As used herein, polyethylene glycol is a genericterm of compounds represented by the formula H(OCH₂CH₂)_(n)OH wherein nis a natural number (compound wherein n is not less than 2000 issometimes referred to as polyethylene oxide).

Examples of colorants used in the formulations of the disclosureinclude, but are not limited to, food colors such as Food Color YellowNo. 5, Food Color Red No. 2, Food Color Blue No. 2 and the like, foodlake colors, red ferric oxide, and yellow ferric oxide.

Examples of pH adjusters used in the formulations of the disclosureinclude, but are not limited to, citric acid or a salt thereof,phosphoric acid or a salt thereof, carbonic acid or a salt thereof,tartaric acid or a salt thereof, fumaric acid or a salt thereof, aceticacid or a salt thereof, and amino acid or a salt thereof.

Examples of surfactants used in the formulations of the disclosureinclude, but are not limited to, sodium lauryl sulfate, polysorbate 80,and polyoxyethylene(160) polyoxypropylene(30)glycol.

Examples of sweeteners used in the formulations of the disclosureinclude, but are not limited to, aspartame (trade name), acesulfamepotassium, sucralose, thaumatin, saccharin sodium, and dipotassiumglycyrrhizinate.

Examples of the flavors used in the formulations of the disclosureinclude, but are not limited to, menthol, peppermint oil, lemon oil, andvanillin.

In some embodiments, the pigments for use herein include, but are notlimited to, titanium dioxide.

In some embodiments, the film former/film coating base is a sugarcoating base. Sugar coating bases for use herein include, but are notlimited to, sucrose in combination with one or more of talc,precipitated calcium carbonate, gelatin, gum arabic, pullulan, orcarnauba wax.

In some embodiments, the film former/film coating base is awater-soluble film coating base. Water-soluble film coating bases foruse herein include, but are not limited to, cellulose polymers such ashydroxypropylcellulose, hydroxypropyl methylcellulose (e.g.,hypromellose 2910, TC-5), hydroxyethylcellulose,methylhydroxyethylcellulose and the like; synthetic polymers such aspolyvinyl acetaldiethylaminoacetate, aminoalkylmethacrylate copolymer E,polyvinylpyrrolidone and the like; and polysaccharides such as pullulanand the like. In some embodiments, the water-soluble film coating baseis hydroxypropyl methylcellulose (e.g., hypromellose 2910, TC-5). Insome embodiments, the film former/film coating base is hydroxypropylmethylcellulose (HPMC). In some embodiments, the hydroxypropylmethylcellulose is hypromellose 2910.

In some embodiments, the film former/film coating base comprisescellulose polymers such as hydroxypropylmethylcellulose phthalate,ethylcellulose, hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L, methacrylicacid copolymer LD, methacrylic acid copolymer S, aminoalkylmethacrylatecopolymer RS, ethyl acrylate-methyl methacrylate copolymer suspension,and the like; and naturally occurring substances such as shellac and thelike.

In some embodiments, the flow aid/polishing agent is carnauba wax. Insome embodiments, the flow aid/polishing agent is talc.

In some embodiments, colorants for use herein include, but are notlimited to, ferric oxide. In some embodiments, the colorant is redferric oxide. In some embodiments, the colorant is yellow ferric oxide.In some embodiments, the colorant is a combination of yellow ferricoxide and red ferric oxide.

In some embodiments, the plasticizers for use herein include, but arenot limited to, polyethylene glycol (e.g., macrogol 6000), triethylcitrate, castor oil, polysorbates, and the like.

In some embodiments, the organic acids for use herein include, but arenot limited to, citric acid, tartaric acid, malic acid, ascorbic acid,and the like.

In some embodiments, the oral formulations of the disclosure, includingthe oral load dose formulations and the oral maintenance doseformulations, comprise at least one excipient that improves stabilitywhile maintaining load capacity. It has been found that for thetreatment of prostate cancer, the oral formulations provided by thisdisclosure that include sodium starch glycolate have improved stabilityand greater load capacity of Compound 1, or a pharmaceuticallyacceptable salt thereof, so that Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof, can be as high as about360 mg in an oral load dose formulation and about 120 mg in an oralmaintenance dose formulation.

The present disclosure provides oral formulations comprising Compound 1,or a pharmaceutically acceptable salt thereof, for the treatment ofprostate cancer. In certain such embodiments, the oral formulationscomprise about 80 mg or about 120 mg or about 160 mg or about 180 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, and core excipients, such as one or more diluents, one ormore binders, one or more disintegrants, one or more lubricants, orcombinations thereof. In certain such embodiments, the diluent comprisesmannitol, the binder comprises hydroxypropyl cellulose, the disintegrantcomprises sodium starch glycolate, and the lubricant compriseshydroxypropyl cellulose. In some embodiments, the oral formulationsfurther comprise one or more film formers/film coating bases, one ormore pigments, one or more colorants, one or more flow aids/polishingagents, or combinations thereof. In certain such embodiments, the filmformer/film coating base comprises hypromellose 2910, the pigmentcomprises titanium dioxide, the colorant comprises ferric oxide, and theflow aid/polishing agent comprises carnauba wax.

In some embodiments, the oral formulations of the disclosure compriseabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, such as about 360 mg orabout 240 mg, and core excipients such as one or more diluents, one ormore binders, one or more disintegrants, one or more lubricants, orcombinations thereof. In certain such embodiments, the diluent comprisesmannitol, the binder comprises hydroxypropyl cellulose, the disintegrantcomprises sodium starch glycolate, and the lubricant compriseshydroxypropyl cellulose. In some embodiments, the oral formulations ofthe disclosure further comprise one or more film formers/film coatingbases, one or more pigments, one or more colorants, one or more flowaids/polishing agents, or combinations thereof. In certain suchembodiments, the film formers/film coating base comprises hypromellose2910, the pigment comprises titanium dioxide, the colorant comprisesferric oxide, and the flow aid/polishing agent comprises carnauba wax.

In some embodiments, the present disclosure provides oral formulationscomprising about 80 mg or about 120 mg or about 160 mg or about 180 mgof Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, and core excipients, namely, 51 mg to 244 mg ofmannitol, 3 mg to 12 mg of hydroxypropyl cellulose, 10 mg to 20 mg ofsodium starch glycolate, and 2 mg to 4 mg of magnesium stearate. In someembodiments, the oral formulations of the disclosure can comprise 80 mgor 120 mg or 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and core excipients, namely,51 mg to 244 mg of mannitol, 3 mg to 12 mg of hydroxypropyl cellulose,10 mg to 20 mg of sodium starch glycolate, and 2 mg to 4 mg of magnesiumstearate. The present disclosure still further provides that such oralformulations include a film coat having film excipients, namely, 7.12 to14.24 mg of hypromellose 2910 (i.e., hydroxypropyl methylcellulose), 0.8mg to 1.6 mg of titanium dioxide, a sufficient quantity of carnauba wax,and 0.08 mg to 0.16 mg of ferric oxide.

In some embodiments, the oral formulations of the disclosure comprise 80mg or 120 mg or 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and core excipients, namely,102 mg to 204 mg of mannitol, 6 mg to 12 mg of hydroxypropyl cellulose,10 mg to 20 mg of sodium starch glycolate, and 2 mg to 4 mg of magnesiumstearate. The present disclosure still further provides that such oralformulations include a film coat having film excipients, namely, 7.12 to14.24 mg of hypromellose 2910 (i.e., hydroxypropyl methylcellulose), 0.8mg to 1.6 mg of titanium dioxide, a sufficient quantity of carnauba wax,and 0.08 mg to 0.16 mg of ferric oxide.

In some embodiments, the oral formulations of the disclosure compriseabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof. Further, in certain suchembodiments, the oral formulations of the disclosure can include: from306 mg to 612 mg of mannitol (including D-mannitol); from 30 mg to 60 mgof sodium starch glycolate; from 18 mg to 36 mg of hydroxypropylcellulose; and from 6 mg to 12 mg of magnesium stearate, as coreexcipients; as well as from 21.36 mg to 42.72 mg of hypromellose 2910;from 2.4 mg to 4.8 mg of titanium dioxide; from 0.24 mg to 0.48 mg offerric oxide; and a sufficient quantity of carnauba wax.

In some embodiments, the oral formulations of the disclosure compriseabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof. Further, in certain suchembodiments, the oral formulations of the disclosure can include: from306 mg to 612 mg of mannitol (including D-mannitol); from 30 mg to 60 mgof sodium starch glycolate; from 18 mg to 36 mg of hydroxypropylcellulose; and from 6 mg to 12 mg of magnesium stearate. In certain suchembodiments, the oral formulations of the disclosure further comprisefrom 21.36 mg to 42.72 mg of hypromellose 2910; from 2.4 mg to 4.8 mg oftitanium dioxide; from 0.24 mg to 0.48 mg of ferric oxide; and asufficient quantity of carnauba wax.

In some embodiments, the oral load dose formulations of the disclosurecomprise about 240 mg, about 320 mg, about 360 mg, or about 480 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, and may be administered once-daily. In some embodiments,the oral load dose formulations comprise about 360 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof.About 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, is used because it optimizesstability in the composition, as well as maintains an efficacious loaddose. In some embodiments, the oral maintenance dose formulations of thedisclosure comprise about 80 mg, about 120 mg, about 160 mg, or about180 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, and may be administered once-daily. In someembodiments, the oral maintenance dose formulations of the disclosurecomprise about 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. About 120 mg of Compound 1, ora corresponding amount of a pharmaceutically acceptable salt thereof, isused because it optimizes stability in the composition, as well asmaintains an efficacious load dose.

Oral maintenance dose formulations of the disclosure comprising Compound1, or a pharmaceutically acceptable salt thereof, can be used fortreating prostate cancer. In certain such embodiments, the oralmaintenance dose formulations of the disclosure comprise about 80 mg toabout 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, such as about 120 mg, and coreexcipients, such as one or more diluents, one or more binders, one ormore disintegrants, one or more lubricants, or combinations thereof. Incertain such embodiments, the diluent comprises mannitol, the bindercomprises hydroxypropyl cellulose, the disintegrant comprises sodiumstarch glycolate, and the lubricant comprises hydroxypropyl cellulose.In some embodiments, the oral maintenance dose formulations furthercomprise one or more film formers/film coating bases, one or morepigments, one or more colorants, one or more flow aids/polishing agents,or combinations thereof. In certain such embodiments, the filmformer/film coating base comprises hypromellose 2910, the pigmentcomprises titanium dioxide, the colorant comprises ferric oxide, and theflow aid/polishing agent comprises carnauba wax. Further, in someembodiments, the oral maintenance dose formulations of the disclosurecan include: from 244 mg to 488 mg of mannitol (including D-mannitol);from 80 mg to 160 mg of microcrystalline cellulose; from 12 mg to 24 mgof hydroxypropyl cellulose; from 20 mg to 40 mg of croscarmellosesodium; from 4 mg to 8 mg of magnesium stearate; from 14.24 mg to 28.48mg of hypromellose 2910; from 1.6 mg to 3.2 mg of titanium dioxide; andfrom 0.16 mg to 0.32 mg of ferric oxide. With this and other oralformulations of the disclosure, water is removed during processing ofthe oral maintenance dose formulation.

In some embodiments, the oral maintenance dose formulation of thedisclosure includes: 17.54 wt % of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof; 53.51 wt % of mannitol;17.54 wt % of microcrystalline cellulose; 2.63 wt % of hydroxypropylcellulose; 4.39 wt % of croscarmellose sodium, and 0.88 wt % ofmagnesium stearate, as core excipients. In certain such embodiments, theoral maintenance dose formulation of the disclosure also includes thefollowing other excipients: 3.12 wt % of hypromellose 2910; 0.35 wt % oftitanium dioxide; and 0.04 wt % of ferric oxide.

In some embodiments, the oral maintenance dose formulations provided bythis disclosure comprise about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof.Further, in certain such embodiments, the oral maintenance doseformulations of the disclosure can include: from 102 mg to 204 mg ofmannitol (including D-mannitol); from 10 mg to 20 mg of sodium starchglycolate; from 6 mg to 12 mg of hydroxypropyl cellulose; from 2 mg to 4mg of magnesium stearate; from 7.12 mg to 14.24 mg of hypromellose 2910;from 0.8 mg to 1.6 mg of titanium dioxide; from 0.08 mg to 0.16 mg offerric oxide; and a sufficient quantity of carnauba wax.

In some embodiments, the oral maintenance dose formulations provided bythis disclosure comprise about 80 mg to about 160 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof.Further, in certain such embodiments, the oral maintenance doseformulations of the disclosure can include: from 102 mg to 204 mg ofmannitol (including D-mannitol); from 10 mg to 20 mg of sodium starchglycolate; from 6 mg to 12 mg of hydroxypropyl cellulose; and from 2 mgto 4 mg of magnesium stearate. In certain such embodiments, the oralmaintenance dose formulations of the disclosure further comprise from7.12 mg to 14.24 mg of hypromellose 2910; from 0.8 mg to 1.6 mg oftitanium dioxide; from 0.08 mg to 0.16 mg of ferric oxide; and asufficient quantity of carnauba wax.

In some embodiments, the oral maintenance dose formulations of thedisclosure include: 38.46 wt % of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof; 49.04 wt % of mannitol;4.81 wt % of sodium starch glycolate (Type A); 2.88 wt % ofhydroxypropyl cellulose; and 0.96 wt % of magnesium stearate, as coreexcipients. In certain such embodiments, the oral maintenance doseformulations of the disclosure also include the following otherexcipients: 3.42 wt % of hypromellose 2910; 0.38 wt % of titaniumdioxide; 0.04 wt % of ferric oxide; and a sufficient quantity ofcarnauba wax.

In some embodiments, the oral maintenance dose formulations of thedisclosure include: 80 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 244 mg of mannitol; 80 mg ofmicrocrystalline cellulose; 12 mg of hydroxypropyl cellulose; 20 mg ofcroscarmellose sodium; 4 mg of magnesium stearate as core excipients. Incertain such embodiments, the oral maintenance dose formulations of thedisclosure also include a film coat including 14.24 mg of hypromellose2910; 1.6 mg of titanium dioxide; and 0.16 mg of ferric oxide.

In some embodiments, the oral maintenance dose formulations of thedisclosure include: 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 366 mg of mannitol(filler/diluent); 120 mg of microcrystalline cellulose (filler/diluent);18 mg of hydroxypropyl cellulose (binder); 30 mg of croscarmellosesodium (disintegrant), and 6 mg of magnesium stearate (lubricant), ascore excipients. In certain such embodiments, the oral maintenance doseformulations of the disclosure also include the following otherexcipients: 21.36 mg of hypromellose 2910 (film coating base); 2.4 mg oftitanium dioxide (pigment); and 0.24 mg of ferric oxide (colorant).

In some embodiments, the oral maintenance dose formulations of thedisclosure include: 160 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 488 mg of mannitol; 160 mg ofmicrocrystalline cellulose; 24 mg of hydroxypropyl cellulose; 40 mg ofcroscarmellose sodium; 8 mg of magnesium stearate as core excipients. Incertain such embodiments, the maintenance dose formulations of thedisclosure also include as a film coat 28.48 mg of hypromellose 2910;3.2 mg of titanium dioxide; and 0.32 mg of ferric oxide.

In some embodiments, the oral maintenance dose formulations provided bythis disclosure include: 80 mg of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof; 102 mg of mannitol; 10 mgof sodium starch glycolate; 6 mg of hydroxypropyl cellulose; 2 mg ofmagnesium stearate; 7.12 mg of hypromellose 2910; 0.8 mg of titaniumdioxide; 0.08 mg of ferric oxide; and a sufficient quantity of carnaubawax.

In some embodiments, the oral maintenance dose formulations provided bythis disclosure include: 120 mg of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof; 153 mg of mannitol(filler/diluent); 15 mg of sodium starch glycolate (disintegrant); 9 mgof hydroxypropyl cellulose (binder); 3 mg of magnesium stearate(lubricant); 10.68 mg of hypromellose 2910 (film coating base); 1.2 mgof titanium dioxide (pigment); 0.12 mg of ferric oxide (colorant); and asufficient quantity of carnauba wax (tablet flow aid/polishing agent).

In some embodiments, the oral maintenance dose formulations provided bythis disclosure include: 160 mg of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof; 204 mg of mannitol; 20 mgof sodium starch glycolate; 12 mg of hydroxypropyl cellulose; 4 mg ofmagnesium stearate; 14.24 mg of hypromellose 2910; 1.6 mg of titaniumdioxide; 0.16 mg of ferric oxide; and a sufficient quantity of carnaubawax.

The disclosure provides oral load dose formulations comprising Compound1, or pharmaceutically acceptable salt thereof, for treatment ofprostate cancer. In certain such embodiments, the oral load doseformulations of the disclosure comprise about 240 mg to about 480 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, such as about 360 mg or 240 mg, and core excipients suchas one or more diluents, one or more binders, one or more disintegrants,one or more lubricants, or combinations thereof. In certain suchembodiments, the diluent comprises mannitol, the binder compriseshydroxypropyl cellulose, the disintegrant comprises sodium starchglycolate, and the lubricant comprises hydroxypropyl cellulose. In someembodiments, the oral load dose formulations of the disclosure furthercomprise one or more film formers/film coating bases, one or morepigments, one or more colorants, one or more flow aids/polishing agents,or combinations thereof. In certain such embodiments, the filmformer/film coating base comprises hypromellose 2910, the pigmentcomprises titanium dioxide, the colorant comprises ferric oxide, and theflow aid/polishing agent comprises carnauba wax. Further, in someembodiments the oral load dose formulations of the disclosure caninclude: from 732 mg to 1464 mg of mannitol (including D-mannitol); from240 mg to 480 mg of microcrystalline cellulose; from 36 mg to 72 mg ofhydroxypropyl cellulose; from 60 mg to 120 mg of croscarmellose sodium;from 12 mg to 24 mg of magnesium stearate; from 42.72 mg to 85.44 mg ofhypromellose 2910; from 4.8 mg to 9.6 mg of titanium dioxide; and from0.48 mg to 0.96 mg of ferric oxide. With this and other oralformulations of the disclosure, water is removed during processing ofthe oral load dose formulation.

In some embodiments, the oral load dose formulations of the disclosureinclude: 17.54 wt % of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 53.51 wt % of mannitol; 17.54wt % of microcrystalline cellulose; 2.63 wt % of hydroxypropylcellulose; 4.39 wt % of croscarmellose sodium; and 0.88 wt % ofmagnesium stearate, as core excipients. In certain such embodiments, theoral load dose formulations of the disclosure also include the followingother excipients: 3.12 wt % of hypromellose 2910; 0.35 wt % of titaniumdioxide; and 0.04 wt % of ferric oxide.

In some embodiments, the oral load dose formulations of the disclosurecomprise about 240 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In certain suchembodiments, the oral load dose formulations of the disclosure caninclude: from 306 mg to 612 mg of mannitol (including D-mannitol); from30 mg to 60 mg of sodium starch glycolate; from 18 mg to 36 mg ofhydroxypropyl cellulose; and from 6 mg to 12 mg of magnesium stearate,as core excipients; as well as from 21.36 mg to 42.72 mg of hypromellose2910; from 2.4 mg to 4.8 mg of titanium dioxide; from 0.24 mg to 0.48 mgof ferric oxide; and a sufficient quantity of carnauba wax.

In some embodiments, the oral load dose formulations of the disclosurecomprise about 240 mg to about 480 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof. In certain suchembodiments, the oral load dose formulations of the disclosure caninclude: from 306 mg to 612 mg of mannitol (including D-mannitol); from30 mg to 60 mg of sodium starch glycolate; from 18 mg to 36 mg ofhydroxypropyl cellulose; and from 6 mg to 12 mg of magnesium stearate.In certain such embodiments, the oral load dose formulations of thedisclosure further comprise from 21.36 mg to 42.72 mg of hypromellose2910; from 2.4 mg to 4.8 mg of titanium dioxide; from 0.24 mg to 0.48 mgof ferric oxide; and a sufficient quantity of carnauba wax.

In some embodiments, the oral load dose formulations of the disclosureinclude: 38.46 wt % of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 49.04 wt % of mannitol; 4.81wt % of sodium starch glycolate (Type A); 2.88 wt % of hydroxypropylcellulose; and 0.96 wt % of magnesium stearate, as core excipients. Incertain such embodiments, the oral load dose formulations of thedisclosure also include the following other excipients: 3.42 wt % ofhypromellose 2910; 0.38 wt % of titanium dioxide; 0.04 wt % of ferricoxide; and a sufficient quantity of carnauba wax.

In some embodiments, the oral load dose formulations of the disclosureinclude: 240 mg of the Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 732 mg of mannitol; 240 mg ofmicrocrystalline cellulose; 36 mg of hydroxypropyl cellulose; 60 mg ofcroscarmellose sodium; 12 mg of magnesium stearate; 42.72 mg ofhypromellose 2910; 4.8 mg of titanium dioxide; and 0.48 mg of ferricoxide.

In some embodiments, the oral load dose formulations of the disclosureinclude: 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 1098 mg of mannitol(filler/diluent); 360 mg of microcrystalline cellulose (filler/diluent);54 mg of hydroxypropyl cellulose (binder); 90 mg of croscarmellosesodium (disintegrant); and 18 mg of magnesium stearate (lubricant), ascore excipients. In certain such embodiments, the oral load doseformulations of the disclosure also include the following otherexcipients: 64.08 mg of hypromellose 2910 (film coating base); 7.2 mg oftitanium dioxide (pigment); and 0.72 mg of ferric oxide (colorant).

In some embodiments, the oral load dose formulation of the disclosureinclude: 480 mg of the Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 1464 mg of mannitol; 480 mg ofmicrocrystalline cellulose; 72 mg of hydroxypropyl cellulose; 120 mg ofcroscarmellose sodium; 24 mg of magnesium stearate; 85.44 mg ofhypromellose 2910; 9.6 mg of titanium dioxide; and 0.96 mg of ferricoxide.

In some embodiments, the oral load dose formulations provided by thisdisclosure include: 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 306 mg of mannitol; 30 mg ofsodium starch glycolate; 18 mg of hydroxypropyl cellulose; 6 mg ofmagnesium stearate; 21.36 mg of hypromellose 2910; 2.4 mg of titaniumdioxide; 0.24 mg of ferric oxide; and a sufficient quantity of carnaubawax.

In some embodiments, the oral load dose formulations provided by thisdisclosure include: 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 459 mg of mannitol(filler/diluent); 45 mg of sodium starch glycolate (disintegrant); 27 mgof hydroxypropyl cellulose (binder); 9 mg of magnesium stearate(lubricant); 32.04 mg of hypromellose 2910 (film coating base); 3.6 mgof titanium dioxide (pigment); 0.36 mg of ferric oxide (colorant); and asufficient quantity of carnauba wax (tablet flow aid/polishing agent).

In some embodiments, the oral load dose formulations provided by thisdisclosure include: 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; 612 mg of mannitol; 60 mg ofsodium starch glycolate; 36 mg of hydroxypropyl cellulose; 12 mg ofmagnesium stearate; 42.72 mg of hypromellose 2910; 4.8 mg of titaniumdioxide; 0.48 mg of ferric oxide; and a sufficient quantity of carnaubawax.

Dosage Packs of the Disclosure

The present disclosure provides for dosage packs comprising the oralload and maintenance dose formulations disclosed herein. The dosage packof the disclosure includes an oral load dose formulation that isseparate from an oral maintenance dose formulation. In certain suchembodiments, the dosage pack is used for treating prostate cancer. Insome embodiments, the oral load dose formulation in the dosage pack hasa different color, shape, and/or size than the oral maintenance doseformulation.

In some embodiments, the dosage pack provided by this disclosureincludes: an oral load dose formulation comprising excipients and fromabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof; and an oral maintenance doseformulation comprising excipients and about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof. In certain such embodiments, the oral load dose andmaintenance formulations independently comprise excipients such as oneor more diluents, one or more binders, one or more disintegrants, one ormore lubricants, or combinations thereof. In certain such embodiments,the diluent comprises mannitol, the binder comprises hydroxypropylcellulose, the disintegrant comprises sodium starch glycolate, and thelubricant comprises hydroxypropyl cellulose. In some embodiments, theoral load dose and maintenance formulations independently furthercomprise one or more film formers/film coating bases, one or morepigments, one or more colorants, one or more flow aids/polishing agents,or combinations thereof. In certain such embodiments, the filmformer/film coating base comprises hypromellose 2910, the pigmentcomprises titanium dioxide, the colorant comprises ferric oxide, and theflow aid/polishing agent comprises carnauba wax.

In some embodiments, the oral load dose formulation of the dosage packof the disclosure comprises 306 mg to 612 mg of mannitol, 18 mg to 36 mgof hydroxypropyl cellulose, 30 mg to 60 mg of sodium starch glycolate,and 6 mg to 12 mg of magnesium stearate.

In some embodiments, the oral load dose formulation of the dosage packof the disclosure further comprises 21.36 mg to 42.72 mg of hypromellose2910, 2.4 mg to 4.8 mg of titanium dioxide, 0.24 mg to 0.48 mg of ferricoxide, and a sufficient quantity of carnauba wax.

In some embodiments, the oral maintenance dose formulation of the dosagepack of the disclosure comprises 102 mg to 204 mg of mannitol, 6 mg to12 mg of hydroxypropyl cellulose, 10 mg to 20 mg of sodium starchglycolate, and 2 mg to 4 mg of magnesium stearate.

In some embodiments, the oral maintenance dose formulation of the dosagepack of the disclosure further comprises 7.12 mg to 14.24 mg ofhypromellose 2910, 0.8 mg to 1.6 mg of titanium dioxide, 0.08 mg to 0.16mg of ferric oxide, and a sufficient quantity of carnauba wax.

In certain aspects of the disclosure, the oral load dose formulation andthe oral maintenance dose formulation of the dosage pack include atleast one excipient that improves stability while maintaining loadcapacity. In some embodiments, the sodium starch glycolate in the oralload dose formulation and the oral maintenance dose formulation of thedosage pack of the disclosure improves stability and load capacity ofCompound 1, or a pharmaceutically acceptable salt thereof, in the oralload dose formulation and the oral maintenance dose formulation.

In some embodiments, the oral load dose formulation of the dosage packof the disclosure comprises about 240 mg, about 320 mg, about 360 mg, orabout 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralload dose formulation of the dosage pack of the disclosure comprisesabout 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralload dose formulation of the dosage pack of the disclosure comprisesabout 240 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof.

In some embodiments, the oral maintenance dose formulation of the dosagepack of the disclosure comprises about 80 mg, about 120 mg, or about 160mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the oral maintenance doseformulation of the dosage pack of the disclosure comprises about 120 mgof Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof.

In some embodiments, the oral load dose formulation of the dosage packof the disclosure comprises about 360 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andthe oral maintenance dose formulation comprises about 120 mg of Compound1, or a corresponding amount of a pharmaceutically acceptable saltthereof.

In some embodiments, the oral load dose formulation of the dosage packof the disclosure comprises about 240 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, andthe oral maintenance dose formulation comprises about 120 mg of Compound1, or a corresponding amount of a pharmaceutically acceptable saltthereof.

In some embodiments, the oral load dose formulation and the oralmaintenance dose formulation of the dosage pack of the disclosure aretablets.

In some embodiments, the oral load dose formulation and the oralmaintenance dose formulation of the dosage pack of the disclosure havean immediate release profile.

In some embodiments, the dosage pack of the disclosure further comprisesat least one of an anti-androgen or CYP17 lyase inhibitor. In certainsuch embodiments, the anti-androgen comprises enzalutamide,bicalutamide, enzalutamide or flutamide, and the CYP17 lyase inhibitorcomprises abiraterone.

Combination Therapy

The administration mode of oral formulations of the disclosurecomprising Compound 1, or a pharmaceutically acceptable salt thereof,and a concomitant medicament can, for example, be (1) an administrationof a single oral formulation obtained by formulating Compound 1, or apharmaceutically acceptable salt thereof, and a concomitant medicament,simultaneously, (2) a simultaneous administration via an identical routeof two formulations obtained by formulating Compound 1, or apharmaceutically acceptable salt thereof, and a concomitant medicamentseparately, and (3) a sequential and intermittent administration via anidentical route of two formulations obtained by formulating Compound 1,or a pharmaceutically acceptable salt thereof, and a concomitantmedicament separately.

In accordance with this disclosure, methods and uses comprisingadministration of oral formulations of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof, can furthercomprise radiation therapy.

In accordance with this disclosure, methods and uses comprisingadministration of oral formulations of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof, can furthercomprise administration of chemotherapy. “Chemotherapy” may refer to acategory of treatment using agents/drugs that are destructive to tumorcells and certain tissues. Examples of such agents/drugs include smallmolecule compounds and biologic drugs, such as an antibody or apolypeptide. Chemotherapy drugs that can be used with the methods anduses described herein include, but are not limited to, alkylatingagents, antimetabolites, anti-tumor antibiotics, topoisomeraseinhibitors, mitotic inhibitors, corticosteroids, differentiating agents,proteasome inhibitors, immunotherapeutics, and hormone therapeutics.Chemotherapy drugs may include, but are not limited to, abirateroneacetate with or without prednisone, enzalutamide, docetaxel,cabazitaxel, mitoxantrone, estramustine, doxorubicin, etoposide,vinblastine, and inhibitors of the enzyme poly adenosine diphosphateribose polymerase (PARP).

In accordance with this disclosure, oral formulations of the disclosurecomprising Compound 1, or a pharmaceutically acceptable salt thereof,can be given daily together with an anti-androgen. The anti-androgen canbe given on and off throughout treatment to provide benefit of ananti-androgen withdrawal syndrome. Alternatively, oral formulationscomprising Compound 1, or a pharmaceutically acceptable salt thereof,can be given on and off throughout the treatment cycle to provide ananti-androgen withdrawal syndrome by itself. To help treat clinicalflare in subjects with prostate cancer, an anti-androgen can beco-administered with an oral formulation of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof. Illustrativeanti-androgens include, but are not limited to, flutamide, nilutamide,bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrolacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide (fluridil), and cimetidine. Suchanti-androgens are typically administered for the first 2 to 4 weeks oftreatment. An illustrative dosage is an oral formulation comprisingabout 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and 160 mg of enzalutamide.

In some embodiments, an oral formulation of the disclosure comprisingCompound 1, or a pharmaceutically acceptable salt thereof, may beadministered with a CYP17 lyase inhibitor. In some embodiments, theCYP17 lysase inhibitor is abiraterone or salts thereof, galeterone orsalts thereof, ketoconazole or salts thereof, or seviteronel or saltsthereof. In certain such embodiments, the CYP17 lyase inhibitorcomprises abiraterone or salts thereof. In some embodiments, the CYP17lyase inhibitor and oral formulation comprising Compound 1, or apharmaceutically acceptable salt thereof, may be administered with aglucocorticoid. In certain such embodiments, the glucocorticoid isprednisone. An illustrative dosing regime is abiraterone acetate givendaily in combination with prednisone given daily. In certain suchembodiments, 1000 mg of abiraterone acetate is given orally once-dailyin combination with 5 mg prednisone given orally twice daily. In someembodiments, the CYP17 lyase inhibitor and oral formulation comprisingCompound 1, or a pharmaceutically acceptable salt thereof, may beadministered in the absence of a glucocorticoid.

In accordance with the treatment methods and uses of this disclosure, ifa prostate cancer is growth hormone dependent, an oral formulation ofthe disclosure comprising Compound 1, or a pharmaceutically acceptablesalt thereof, may be administered in combination with a growth hormone(receptor) antagonist, or Prolactin (receptor) antagonist, or otherdrugs that may decrease growth hormone or IGF-1.

Still another benefit of this disclosure is that an oral formulation ofthe disclosure comprising Compound 1, or a pharmaceutically acceptablesalt thereof, may be administered to a subject in conjunction with oneor more interventions that mitigate or avoid side-effects normallyassociated with a GnRH antagonist, such as bone mineral density (BMD)loss. Interventions include life style interventions and pharmacologicinterventions. Such life style interventions include, but are notlimited to, exercise, smoking abstinence, and alcohol abstinence. Suchpharmacologic interventions include, but are not limited to, calciumsupplementation, vitamin D supplementation, bisphosphonates, denosumab,calcitonin, SERMs, and strontium.

In some embodiments, the methods and uses provided herein do not includeadministering Compound 1 or a pharmaceutically acceptable salt thereofwithin 6 hours of administering a P-glycoprotein (P-gp) inhibitor, CYP3Ainducer, or a P-gp inducer, or any combinations thereof. P-gp mediatesthe export of drugs from certain cells, such as those located in thesmall intestine, blood-brain barrier, hepatocytes, and kidney proximaltube. P-gp may be affected by P-gp inducers or inhibitors, which impairP-gp mediated uptake or efflux, or enhance P-gp activity, respectively.CYP3A is a subfamily of monooxygenases which may be involved in drugmetabolism. P-gp or CYP3A inducers may include carbamazepine, rifampin,St. John's wort, bosentan, efavirenz, mitotane, modafinil, or nafcillin.P-gp inhibitors may include amiodarone, azithromycin, captopril,carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem,dronedarone, eliglustat, erythromycin, felodipine, itraconazole,ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quercetin,quinidine, reserpine, ranolazine, saquinavir, telaprevir, tipranavir,ticagrelor, tacrolimus, and verapamil. A discussion of the P-gptransport system may be found in J. D. Wesslery, et al. JACC (2013)61(25): 2495-502. In some embodiments, Compound 1 or a pharmaceuticallyacceptable salt thereof is administered no less than 6 hours, no lessthan 8 hours, no less than 10 hours, or no less than 12 hours before aP-gp inhibitor, CYP3A inducer, or a P-gp inducer, or any combinationsthereof is administered. In some embodiments, Compound 1 or apharmaceutically acceptable salt thereof is administered no less than 6hours, no less than 8 hours, no less than 10 hours, or no less than 12hours after a P-gp inhibitor, CYP3A inducer, or a P-gp inducer, or anycombinations thereof is administered. In certain embodiments, forexample when beginning a treatment comprising administration of Compound1 or a pharmaceutically acceptable salt thereof, Compound 1 or apharmaceutically acceptable salt thereof is administered no less than 16hours, no less than 20 hours, or no less than 24 hours before a P-gpinhibitor, CYP3A inducer, or a P-gp inducer, or any combinations thereofis administered. In other embodiments, for example when beginning atreatment comprising administration of Compound 1 or a pharmaceuticallyacceptable salt thereof, Compound 1 or a pharmaceutically acceptablesalt thereof is administered no less than 16 hours, no less than 20hours, or no less than 24 hours after a P-gp inhibitor, CYP3A inducer,or a P-gp inducer, or any combinations thereof is administered.

Pharmacokinetics

In some embodiments, Compound 1, or a pharmaceutically acceptable saltthereof, is formulated to achieve a desired PK profile, such aseffective plasma levels for once-daily treatment with a low dose ofCompound 1, or a pharmaceutically acceptable salt thereofPharmacokinetic characteristics were determined in healthy subjectsafter single or repeat-dose administration (once per day, untilpharmacokinetic steady-state is reached, at least as long as 5half-lives). The effect of food or meals was determined after asingle-dose administration, where the pharmacokinetics of Compound 1before/with/after food is compared to administration in the fasted state(no food for at least 8 hours prior to dosing and for 4 hours afterdosing). After administration of Compound 1, blood samples atprespecified intervals were collected, plasma is harvested, and theconcentration of Compound 1 is determined using analytical methods suchas high-performance liquid chromatography with tandem mass-spectrometry.Pharmacokinetic parameters (such as C_(max), AUC and half-life) weredetermined from plasma concentration-time data for each individualsubject using noncompartmental analysis methods, as implemented insoftware such as Phoenix WinNonlin. These parameters may then besummarized or compared using statistical methods.

In some embodiments, a “high-bioavailability formulation” dosage formcomprising about 120 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, taken orally pre-prandiallymay provide a blood plasma concentration of at least about 22.68 ng/mLat 1 hour after dose administration. In some embodiments, it may providea blood plasma concentration of about 48.6 ng/mL at 1 hour after doseadministration. In certain embodiments, it may provide a blood plasmaconcentration of about 84 ng/mL at 1 hour after dose administration. Insome embodiments, the high-bioavailability formulation may have a lowerdose of Compound 1, or a pharmaceutically acceptable salt thereof, yetmay achieve the same average drug exposure in subjects.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltthereof, may be formulated to achieve a low variability ofpharmacokinetic and pharmacodynamic effects in subjects. In someembodiments, a “low variability formulation” dosage form comprisingabout 40 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, taken orally pre-prandiallymay provide pharmacodynamic effects that are less subject to variationin subjects, yet may achieve the same average drug exposure in subjectsas in other embodiments described herein.

In some embodiments, an oral load dose formulation tablet comprisingabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, and an oral maintenance doseformulation tablet comprising about about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, are formulated so that both are high-bioavailability andfood-independent, and may provide pharmacokinetic and pharmacodynamiceffects that are less subject to variation in subjects.

In some embodiments, an oral load dose formulation tablet comprisingabout 360 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof, and an oral maintenance doseformulation tablet comprising about 120 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, areformulated so that both are high-bioavailability and food-independent,and may provide pharmacokinetic and pharmacodynamic effects that areless subject to variation in subjects.

In some embodiments, a patient can take an oral formulation comprisingCompound 1, or a pharmaceutically acceptable salt thereof, before orafter a meal, which requires that consuming a meal has a minimum effecton the mean plasma AUC relative to the fasting state. In someembodiments, a “food-independent formulation” oral maintenance doseformulation comprising about 120 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, taken orally mayhave a ratio of the mean plasma AUC for fed-state administrationrelative to fasted-state administration [mean plasma AUC_((fed))/meanplasma AUC_((fasted))] that is 0.9 to 1.1, such as 0.95 to 1.05 or 1. Insome embodiments, the mean plasma AUC_((fed))/mean plasma AUC_((fasted))is 0.8 to 1.25.

The present disclosure provides a method or use for treating prostatecancer that includes administering to the subject at least once dailyfor 24 consecutive weeks or greater for a treatment period, an oralformulation comprising at least about 80 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, in adosage form that may achieve a pharmacokinetic (PK) profile in which thearea under the plasma drug concentration-time curve (AUC_((0-tau)))increases at least 1.5 fold or 2 fold or greater when measured from thefirst to last day of the treatment period. In certain such embodiments,the AUC_((0-tau)) may increase at least 1.5 fold when measured from thefirst to last day of the treatment period. In certain such embodiments,the AUC_((0-tau)) may increase at least 2 fold or greater when measuredfrom the first to last day of the treatment period.

The present disclosure also provides a method or use for treatingprostate cancer in a subject, the method or use including: administeringto the subject for at least one day for a first treatment period, anoral load dose formulation comprising about 240 mg to about 480 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof; and administering to the subject at least once daily for24 consecutive weeks or greater for a second treatment period, an oralmaintenance dose formulation having about 80 mg to about 160 mg ofCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, and the oral maintenance dose formulation has a PK profilein which mean plasma AUC_((0-tau)) may increase at least 1.5 fold or 2fold or greater when measured from the first day of the first treatmentperiod to last day of the second treatment period. In certain suchembodiments, the oral maintenance dose formulation has a PK profile inwhich mean plasma AUC_((0-tau)) may increase at 2 fold or greater whenmeasured from the first to last day of the treatment period.

The present disclosure still further provides a method or use forsuppressing one or more sex hormones in a subject having prostate cancerthat includes: administering to the subject at least once daily for 24consecutive weeks or greater for a treatment period, an oral formulationcomprising at least about 80 mg of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof, in a dosage form that mayachieve a PK profile in which mean plasma AUC_((0-tau)) may increase atleast 1.5 fold or 2 fold or greater when measured from the first to lastday of the treatment period. In certain such embodiments, theAUC_((0-tau)) may increase at least 1.5 fold when measured from thefirst to last day of the treatment period. In certain such embodiments,the AUC_((0-tau)) may increase at least 2 fold or greater when measuredfrom the first to last day of the treatment period.

The present disclosure provides a method or use for suppressing one ormore sex hormones in a subject having prostate cancer that includes:administering to the subject for at least one day for a first treatmentperiod, an oral load dose formulation comprising about 240 mg to about480 mg of Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof; and administering to the subject at least oncedaily for 24 consecutive weeks or greater for a second treatment period,an oral maintenance dose formulation having about 80 mg to about 160 mgof Compound 1, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, and the oral maintenance dose formulation has aPK profile in which mean plasma AUC_((0-tau)) may increase at least 1.5fold or 2 fold or greater, when measured from the first day of the firsttreatment period to last day of the second treatment period. In certainsuch embodiments, the AUC_((0-tau)) may increase at least 2 fold orgreater when measured from the first to last day of the treatmentperiod.

The present disclosure further provides a method or use for treatingprostate cancer that includes administering to the subject at least oncedaily for 24 consecutive weeks or greater for the treatment period, anoral formulation comprising at least about 80 mg of Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof, in adosage form to achieve a PK profile in which mean C_(max) may increaseat least 2 fold when measured from the first to last day of thetreatment period.

The present disclosure further provides a method or use for treatingprostate cancer that includes: administering to the subject for at leastone day for a first treatment period, an oral formulation comprisingabout 240 mg to about 480 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof; and administering to thesubject at least once daily for 24 consecutive weeks or greater for asecond treatment period, the oral maintenance dose formulationcomprising about 80 mg to about 160 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof, and the oralmaintenance dose formulation has a PK profile in which mean C_(max) mayincrease at least 2 fold when measured from the first day of the firsttreatment period to last day of the second treatment period.

The present disclosure also provides a method or use for suppressing oneor more sex hormones in a subject having prostate cancer that includesadministering to the subject at least once daily for 24 consecutiveweeks or greater for the treatment period, an oral formulationcomprising at least about 80 mg of Compound 1, or a corresponding amountof a pharmaceutically acceptable salt thereof, in a dosage form toachieve a PK profile in which mean C_(max) may increase at least 2 foldwhen measured from the first to last day of the treatment period.

The present disclosure further provides a method or use for suppressingone or more sex hormones in a subject having prostate cancer, whichincludes: administering to the subject for at least one day for a firsttreatment period, or oral load dose formulation comprising about 240 mgto about 480 mg of Compound 1, or a corresponding amount of apharmaceutically acceptable salt thereof; and administering to thesubject at least once daily for 24 consecutive weeks or greater for asecond treatment period, an oral maintenance dose formulation comprisingabout 80 mg to about 160 mg of Compound 1, or a corresponding amount ofa pharmaceutically acceptable salt thereof, and the oral maintenancedose formulation has a PK profile in which mean C_(max) may increase atleast 2 fold when measured from the first day of the first treatmentperiod to last day of the second treatment period.

In some embodiments, several benefits may result from pre-prandialadministration of an oral formulation comprising Compound 1, or acorresponding amount of a pharmaceutically acceptable salt thereof. Insome embodiments, mean C_(max) may be higher with pre-prandialadministration than with post-prandial administration. Also, mean plasmaAUC_((0-tau)) may be higher with pre-prandial administration than withpost-prandial administration after at least 30 minutes.

Several benefits may result from treating prostate cancer byadministering oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, to a subject in need oftreatment. In some embodiments, mean C_(max) may be achieved between 1and 2 hours (T_(max)) after beginning treatment. Mean plasma T_(1/2) maybe 30 to 70 hours measured at day 14 after beginning treatment. Steadystate may be reached within 10 days after beginning treatment. Less than4% of Compound 1 may be excreted unchanged in urine of a subject,measured at day 14 after beginning treatment. Medical castration levelsof less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone maybe achieved and maintained from day 14 to day 28 after beginningtreatment.

Additional benefits that may result from treating prostate cancer byadministering oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, to a subject include, forexample, mean plasma AUC_((0-tau)) may increase 1.5 to 2.5 fold (150% to250%) from day 1 to day 14 after beginning treatment. In someembodiments, mean C_(max) may increase 1.5 to 2.5 fold (150% to 250%)from day 1 to day 14 after beginning treatment.

Additional benefits that may result from treating prostate cancer byadministering oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof, to a subject include, forexample, mean plasma AUC_((0-tau)) may increase 1.5 to 2.5 fold (150% to250%) from day 1 to day 14 after beginning treatment. In someembodiments, mean C_(max) may increase 1.5 to 2.5 fold (150 to 250%)from day 1 to day 14 after beginning treatment.

In accordance with this disclosure, the mean plasma T_(1/2) of Compound1 may be at least 15 hours, at least about 30 hours, or at least about35 hours, measured at the end of the treatment period. In someembodiments, the mean plasma T_(1/2) of Compound 1 may be about 35 hoursto about 45 hours, such as about 37 hours to about 42 hours, measured atthe end of the treatment period.

Following administering oral maintenance dose formulations comprisingabout 80 mg or about 120 mg per day for 25 consecutive weeks of theCompound 1, or a corresponding amount of a pharmaceutically acceptablesalt thereof, formulation, median trough plasma concentration (C_(min))of unchanged Compound 1 may range between 1.0 ng/mL and 9.0 ng/mL,particularly between 2.0 ng/mL and 8.0 ng/mL, and more particularlybetween 2.5 ng/mL and 7.5 ng/mL, for the 80 mg dose, and between 2.0ng/mL and 14.0 ng/mL, particularly between 4.0 ng/mL and 12.0 ng/mL, andmore particularly between 4.5 ng/mL and 11.5 ng/mL, for the 120 mg dose.

In some embodiments, C_(min) may be maintained constant over thetreatment period.

As described herein, in some embodiments, the absorption of Compound 1in plasma may be decreased and delayed following a single doseadministered 30 minutes after the start of a standard U.S. Food and DrugAdministration (FDA) high fat, high-calorie breakfast (approx. 800-1000calories, 50% from fat) compared to fasting conditions. Median T_(max)may increase under fed conditions. Mean C_(max) and mean plasma AUC_(∞)may be reduced under fed conditions compared with fasted conditions,indicating a clinically meaningful effect of food on the oralbioavailability of Compound 1. When Compound 1, or a pharmaceuticallyacceptable salt thereof, may be administered daily 30 minutes prior toingestion of a standardized morning meal (approx. 600 calories, 27% fromfat), systemic exposure to Compound 1 may be reduced to a lesser extentand no obvious changes in the rate of absorption are observed whencompared to fasting conditions. In some embodiments, subjects shouldtake oral formulations comprising Compound 1, or a pharmaceuticallyacceptable salt thereof, upon arising in the morning, on an emptystomach, and start eating approximately 30 minutes after dosing wheneverpossible.

Following administration of oral maintenance dose formulationscomprising about 80 mg or about 120 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof (“Compound 1formulation”), per day for 13 consecutive weeks having the followingexcipients: 244 mg or 549 mg of mannitol, 40 mg or 90 mg ofmicrocrystalline cellulose, 12 mg or 27 mg of hydroxypropyl cellulose,20 mg or 45 mg of croscarmellose sodium, 4 mg or 10 mg of magnesiumstearate, 14.24 mg or 35.6 mg of hypromellose 2910, 1.6 mg or 3.6 mg oftitanium dioxide, and 0.16 mg or 0.36 mg of ferric oxide, the changefrom baseline (i.e., the subject's serum PSA level prior to treatmentcommencing) in the mean serum PSA concentration at 13 consecutive weeks(i.e., week 13, day 1) may be a reduction from 10.6004 ng/L to 1.0823ng/L (i.e., 10.6 fold (1060%) reduction) for the 80 mg dose, and areduction from 6.6275 ng/L to 0.5849 ng/L (i.e., 11.3 fold (1130%)reduction) for the 120 mg dose. The change from baseline in the meanserum PSA concentration may result in a 6.5 to 15.5 fold (650% to1550%), particularly a 7.5 to 14.5 fold (750% to 1450%), and moreparticularly a 8.0 to 12 fold (800% to 1200%), reduction for the 80 mgdose and a 7.5 to 16.5 fold (750% to 1650%), particularly a 8.5 to 15.5fold (850% to 1550%), and more particularly a 9.0 to 13 fold (900% to1300%), reduction for the 120 mg dose. Rates of PSA reduction achievedby the Compound 1, or a pharmaceutically acceptable salt thereof,formulations may be comparable to leuprolide acetate and degarelix, butthe Compound 1, or a pharmaceutically acceptable salt thereof,formulations provide greater ease of use.

Following administration of oral maintenance dose formulationscomprising about 80 mg or about 180 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof (“Compound 1formulation”), per day for 16 consecutive days, the change from baseline(i.e., the subject's serum LH level prior to treatment commencing) inthe mean serum LH concentration at the end of 16 consecutive days,namely end of treatment, may be a reduction from 3.90 IU/L to 0.23 IU/L(i.e., 13.8 fold (1380%) reduction) for 180 mg dose, and a reductionfrom 4.57 IU/L to 0.33 IU/L (i.e., 17 fold (1700%) reduction) for 80 mgdose. The change from baseline in the mean serum LH concentration mayresult in a 10 to 18 fold (1000% to 1800%), particularly a 12 to 16 fold(1200% to 1600%), and more particularly a 12.5 to 15.5 fold (1250% to1550%), reduction for the 80 mg dose, and a 14 to 20 fold (1400% to2000%), particularly a 15 to 19 fold (1500% to 1900%), and moreparticularly a 15.5 to 18.5 fold (1550% to 1850%), reduction for the 180mg dose.

Following administration of oral maintenance dose formulationscomprising about 80 mg or about 180 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof (“Compound 1formulation”), per day for 16 consecutive days, the change from baseline(i.e., the subject's serum testosterone level prior to treatmentcommencing) in the mean serum testosterone concentration at the end of16 consecutive days may be a reduction from 10.40 nmol/L to 0.3565nmol/L (i.e., 29 fold (2900%) reduction) for the 80 mg dose, and areduction from 10.40 nmol/L to 0.4320 nmol/L (i.e., 24 fold (2400%)reduction) for the 180 mg dose. The change from baseline in the meanserum testosterone concentration may result in a 25 to 33 fold (2500% to3300%), particularly a 27 to 31 fold (2700% to 3100%), and moreparticularly a 27.5 to 30.5 fold (2750% to 3050%), reduction for the 80mg dose, and a 20 to 28 fold (2000% to 2800%), particularly a 22 to 26fold (2200% to 2600%), and more particularly a 22.5 to 25.5 fold (2250%to 2550%), reduction for the 180 mg dose. Rates of testosteronesuppression achieved by the Compound 1, or a pharmaceutically acceptablesalt thereof, formulations may be comparable to leuprolide acetate anddegarelix, but the Compound 1, or a pharmaceutically acceptable saltthereof, formulations provide greater ease of use.

Following administration of oral maintenance dose formulationscomprising about 80 mg or about 180 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof (“Compound 1formulation”), per day for 16 consecutive days, change from baseline inmean serum FSH concentration at the end of 16 consecutive days may be areduction from 6.07 IU/L to 0.67 IU/L (i.e., 9.1 fold (910%) reduction)for the 80 mg dose, and a reduction from 3.88 IU/L to 0.33 IU/L (i.e.,11.8 fold (1180%) reduction) for the 180 mg dose. The change frombaseline in mean serum FSH concentration may result in a 5 to 13 fold(500% to 1300%), particularly a 7 to 11 fold (700% to 1100%), and moreparticularly a 7.5 to 10.5 fold (750% to 1050%), reduction for the 80 mgdose, and a 8 to 16 fold (800% to 1600%), particularly a 10 to 14 fold(1000% to 1400%), and more particularly a 10.5 to 13.5 fold (1050% to1350%), reduction for the 180 mg dose.

Following administration of oral maintenance dose formulationscomprising about 80 mg or about 180 mg of Compound 1, or a correspondingamount of a pharmaceutically acceptable salt thereof (“Compound 1formulation”), per day for 16 consecutive days, the change from baseline(i.e., the subject's serum DHT level prior to treatment commencing) inthe mean serum DHT concentration at the end of the 16 consecutive daysmay be a reduction from 1.883 nmol/L to 1.095 nmol/L (i.e., 1.7 fold(170%) reduction) for the 80 mg dose, and a reduction from 1.882 nmol/Lto 0.865 nmol/L (i.e., 2.2 fold (220%) reduction) for the 180 mg dose.The change from baseline in the mean serum DHT concentration may resultin a 1.1 to 5 fold (110% to 500%), particularly a 1.1 to 3 fold (110% to300%), and more particularly a 1.1 to 2.5 fold (110% to 250%), reductionfor the 80 mg dose, and a 1.1 to 6 fold (110% to 600%), particularly a1.1 to 4 fold (110% to 400%), and more particularly a 1.1 to 3.5 fold(110% to 350%), reduction for the 180 mg dose.

The following non-limiting examples are provided to illustrate thedisclosure.

EXAMPLES Example 1: Production of Compound 1

N-(4-(1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(150 mg, 0.259 mmol) was dissolved in DMF (4 mL), and methyl iodide(0.010 mL, 0.164 mmol) was added thereto. The reaction mixture wasstirred at room temperature for 1 hour, combined with an aqueoussolution of sodium hydrogen carbonate and extracted with ethyl acetate.The organic layer was washed with brine, dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent:ethyl acetate/methanol=40/1),and recrystallized from dichloromethane/methanol/diethyl ether to givethe title compound (17.3 mg, 17%) as colorless crystals. ¹H-NMR (CDCl₃)δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H),6.92 (2H, t, J=8.2 Hz), 7.12 (1H, d, J=8.8 Hz), 7.2-7.65 (7H, m), 7.69(1H, s).

Example 2: Production of Film Coated Tablets of Compound 1

Film coated tablets were prepared by using the compound obtained inExample 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (120mg), hydroxypropyl cellulose (18 mg), croscarmellose sodium (30 mg),magnesium stearate (6 mg), and sufficient quantity of purified water.Water was removed during processing. In a fluid bed dryer granulator(LAB-1, Powrex Corporation), the compound obtained in Example 1,mannitol, precisely D-mannitol, and microcrystalline cellulose werepreheated and mixed, an aqueous solution of hydroxypropyl cellulose wassprayed, and the mixture was dried to give a granulated powder. To theobtained granulated powder was added croscarmellose sodium and magnesiumstearate, and they were mixed in a bag to give a mixed powder. The mixedpowder was tableted by a rotary tableting machine (compact 10 tabletingmachine, Kikusui Seisakusho Ltd.) with a 6.0 mmφ pounder to give coretablets. The core tablets were placed in a film coating machine(DRC-200, Powrex Corporation), a film coating solution with acomposition of hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg),and red ferric oxide (0.24 mg) was sprayed to give film coated tablets.The obtained film coated tablets were placed in a glass bottle, whichwas tightly sealed and preserved at 60° C. for 2 weeks.

Example 3: Production of Film Coated Tablets of Compound 1

Film coated tablets were prepared by using the compound obtained inExample 1 (360 mg), mannitol (1098 mg), microcrystalline cellulose (360mg), hydroxypropyl cellulose (54 mg), croscarmellose sodium (90 mg),magnesium stearate (18 mg), and sufficient quantity of purified water.Water was removed during processing. In a fluid bed dryer granulator(LAB-1, Powrex Corporation), the compound obtained in Example 1,mannitol, precisely D-mannitol, and microcrystalline cellulose werepreheated and mixed, an aqueous solution of hydroxypropyl cellulose wassprayed, and the mixture was dried to give a granulated powder. To theobtained granulated powder was added croscarmellose sodium and magnesiumstearate, and they were mixed in a bag to give a mixed powder. The mixedpowder was tableted by a rotary tableting machine (compact 10 tabletingmachine, Kikusui Seisakusho Ltd.) with a 6.0 mmφ pounder to give coretablets. The core tablets were placed in a film coating machine(DRC-200, Powrex Corporation), a film coating solution with acomposition of hypromellose 2910 (64.08 mg), titanium dioxide (7.2 mg),and red ferric oxide (0.72 mg) was sprayed to give film coated tablets.The obtained film coated tablets were placed in a glass bottle, whichwas tightly sealed and preserved at 60° C. for 2 weeks.

Example 4: Production of Film Coated Tablets of Compound 1

Film coated tablets were prepared by using the compound obtained inExample 1 (120 mg), mannitol (153 mg), sodium starch glycolate (Type A)(15 mg), hydroxypropyl cellulose (9 mg), magnesium stearate (3 mg), anda sufficient quantity of purified water. Again, water was removed duringprocessing. In a fluid bed dryer granulator (LAB-1, Powrex Corporation),the compound obtained in Example 1, D-mannitol, and sodium starchglycolate were preheated and mixed, an aqueous solution of hydroxypropylcellulose was sprayed, and the mixture was dried to give a granulatedpowder. To the obtained granulated powder, magnesium stearate was added,and they were mixed in a bag to give a mixed powder. The mixed powderwas tableted by a rotary tableting machine (compact 10 tabletingmachine, Kikusui Seisakusho Ltd.) with a 6.0 mmφ pounder to give coretablets. The core tablets were placed in a film coating machine(DRC-200, Powrex Corporation), a film coating solution with acomposition of hypromellose 2910 (10.68 mg), titanium dioxide (1.2 mg),ferric oxide (0.12 mg), and a sufficient quantity of carnauba wax, wassprayed to give film coated tablets. The obtained film coated tabletswere placed in a glass bottle, which was tightly sealed and preserved at60° C. for 2 weeks.

Example 5: Production of Film Coated Tablets of Compound 1

Film coated tablets were prepared by using the compound obtained inExample 1 (360 mg), mannitol (459 mg), sodium starch glycolate (Type A)(45 mg), hydroxypropyl cellulose (27 mg), magnesium stearate (9 mg), anda sufficient quantity of purified water. Again, water was removed duringprocessing. In a fluid bed dryer granulator (LAB-1, Powrex Corporation),the compound obtained in Example 1, D-mannitol, and sodium starchglycolate were preheated and mixed, an aqueous solution of hydroxypropylcellulose was sprayed, and the mixture was dried to give a granulatedpowder. To the obtained granulated powder, magnesium stearate was added,and they were mixed in a bag to give a mixed powder. The mixed powderwas tableted by a rotary tableting machine (compact 10 tabletingmachine, Kikusui Seisakusho Ltd.) with a 6.0 mmφ pounder to give coretablets. The core tablets were placed in a film coating machine(DRC-200, Powrex Corporation), a film coating solution with acomposition of hypromellose 2910 (32.04 mg), titanium dioxide (3.6 mg),ferric oxide (0.36 mg), and a sufficient quantity of carnauba wax, wassprayed to give film coated tablets. The obtained film coated tabletswere placed in a glass bottle, which was tightly sealed and preserved at60° C. for 2 weeks.

Example 6: A Study to Evaluate the Effect of Compound 1 onPharmacokinetics and Pharmacodynamics in Men with Non-MetastaticProstate Cancer

This study consisted of two parts: Part A, a dose-rising phase, and PartB, an expansion phase. Whether or not the study would proceed to thenext cohort or to Part B was determined through assessment oftolerability at the present dose, based on the incidence of adverseeffects during the evaluation period.

The Compound 1 formulation was taken orally once a day for 28 days. The120 mg Compound 1 formulation comprised a core tablet of Compound 1 (120mg), mannitol (366 mg), microcrystalline cellulose (60 mg),hydroxypropyl cellulose (18 mg), croscarmellose sodium (30 mg), andmagnesium stearate (6 mg). The core tablets were coated with a filmcoating comprising hypromellose 2910 (21.36 mg), titanium dioxide (2.4mg), and red ferric oxide (0.06 mg). The amounts of the excipients inthe core tablet and film coating were adjusted accordingly based on theamount of Compound 1 in the core tablet (e.g., for the 360 mg tablet,the amount of excipient added to the core tablet and film coating isthree times the amount added to the 120 mg tablet).

Subjects in Cohort 1 received a load dose of 320 mg and a maintenancedose of 80 mg; subjects in Cohort 2 received a load dose of 320 mg and amaintenance dose of 120 mg; subjects in Cohort 3 received a load dose of320 mg and a maintenance dose of 160 mg; and subjects in Cohort 4received a load dose of 360 mg and a maintenance dose of 120 mg.Subjects being switched to treatment with GnRH agonists (e.g.,leuprolide acetate) or GnRH antagonists (e.g., degarelix) go through a1-week follow-up period after receiving their last dose of the Compound1 formulation.

If tolerability was confirmed in Cohort 2, then the study proceeded toCohort 3 and Part B simultaneously. However, if tolerability was notconfirmed in Cohort 2, then an additional cohort was conducted, wheresubjects received a load or loading dose of Compound 1 of 320 mg and amaintenance dose of 40 mg. Cohort 4 was conducted after tolerability wasconfirmed in Cohort 3.

In Part B, subjects were randomized in a 1:1 ratio (15 patients each) toeither the 80 mg group (load dose of Compound 1 320 mg and maintenanceof 80 mg orally once-daily) or 120 mg group (load dose of Compound 1 320mg and maintenance dose of 120 mg orally once-daily) to evaluate thesafety of the Compound 1 formulation. In addition to the safetyassessments, efficacy assessments were also performed according to thestudy schedule, and the Compound 1 formulation was administered untileach subject met the discontinuation criteria.

The serum concentrations of testosterone and other pharmacodynamicparameters involved in the testosterone synthetic pathway, such as LH,FSH, DHT and SHBG, were measured during 28 days of the treatment periodin Part A and for up to 96 weeks in Part B. Assay methods of serumtestosterone, LH and FSH are chemiluminescent immunoassay (CLIA) (lowerlimits of quantitation [LLOQ] were 0.04 ng/mL, 0.10 mIU/mL, and 0.10mIU/mL, respectively), DHT was radioimmunoassay (MA) of ammonium sulfatesalting out (LLOQ was 0.02 ng/mL), and SHBG was two-side CLIA (LLOQ was2.0 nmol/L).

For Part A, the mean serum testosterone concentration of each dose levelof Compound 1 is shown in FIG. 1, and individual changes in the serumtestosterone concentration of each dose level of the study drug ispresented in FIG. 2. The serum testosterone concentration rapidlydecreased after the first dose in all dose levels (maintenance dose of80 mg, 120 mg or 160 mg). The mean serum testosterone concentration fellto below medical castration levels (i.e., below 50 ng/dL) within thefirst 3 days of dosing. The serum testosterone concentration achievedmedical castration levels between Day 2 and Day 14 and was maintainedthereafter up to 3 days after the last dose on Day 28 in all subjects.

For Part A, the mean serum LH, FSH, DHT and SHBG concentrations for eachdose level of the study drug are graphically shown in FIGS. 3-6,respectively. The serum LH, FSH and DHT concentrations were rapidlysuppressed, similar to the serum testosterone concentration, in all doselevels. There were no particular changes between the baseline (i.e., thesubject's serum hormone levels prior to treatment commencing) andpostdose serum SHBG concentrations.

For Part B, the mean serum testosterone concentration for each doselevel of the study drug is shown in FIG. 7, and changes in the serumtestosterone concentration for each dose level of the study drug isshown in FIG. 8A and FIG. 8B, and summary statistics of serumtestosterone concentrations is shown in FIG. 2. The serum testosteroneconcentration was rapidly suppressed after the first dose in all doselevels (maintenance dose of 80 mg or 120 mg). The mean serumtestosterone concentration was suppresssed to below medical castrationlevels (i.e., below 50 ng/dL) within the first 4 days of dosing. In allsubjects, the serum testosterone concentration reached medicalcastration levels between Day 2 and Week 3. Medical castration levelswere maintained in all subjects throughout the evaluation period.

For Part B, the mean serum LH, FSH, DHT and SHBG concentrations for eachdose level of the study drug are shown graphically in FIGS. 9-12,respectively. The serum LH, FSH and DHT concentrations were rapidlysuppressed, similar to the serum testosterone concentration, in all doselevels. There were no particular changes in the baseline and postdoseserum SHBG concentrations.

To evaluate the clinical efficacy of Compound 1 on prostate cancer, theserum concentration of PSA, the established diagnostic marker forprostate cancer, was measured during the 28 days of treatment period inPart A and for up to 96 weeks in Part B. The assay method of PSA was achemiluminescent enzyme immunoassay (CLEIA) and LLOQ was 0.008 ng/mL.

For Part A, at Day 28, the mean and median percentage changes frombaseline in the serum PSA concentration were −76.37% and −77.50%,respectively, in Cohort 1, −60.10% and −72.30%, respectively, in Cohort2, and −32.10% and −50.50%, respectively, in Cohort 3. For Part A,summary statistics of serum PSA and change from baseline in PSA aretabulated in FIG. 13.

For Part B, the mean and median percentage changes from baseline in theserum PSA concentration at Week 13 Day 1 (LOCF) were −89.47% and−97.20%, respectively, in the 80 mg group and −93.11% and −95.80%,respectively, in the 120 mg group. For Part B, summary statistics ofserum PSA and change from baseline in PSA are tabulated in FIG. 14.

Following administering to Week 13 Day 1 in Part B, the change frombaseline in mean serum PSA concentration at Week 13 Day 1 is 10.6 fold(1060%) reduction for 80 mg dosage (reduced from 10.6004 ng/L to 1.0823ng/L), and 11.3 fold (1130%) reduction for 180 mg dosage (reduced from6.6275 ng/L to 0.5849 ng/L).

To preliminarily assess the pharmacokinetics of Compound 1, the plasmaconcentration of unchanged Compound 1 was measured by validated LC-MS/MSmethod (LLOQ: 0.01 ng/mL) in patients with prostate cancer when thestudy drug was repeatedly administered.

For Part A, the Compound 1 formulation was administered once-daily for28 days. The profiles of plasma unchanged Compound 1 concentration−timeat Day 1 (loading dose) and Days 14 and 28 (maintenance dose) are shownin FIG. 15A-15C, and preliminary pharmacokientic parameters aresummarized in FIG. 16.

At Day 1, a load dose of 320 mg was orally administered. The plasmaconcentration of unchanged Compound 1 rapidly increased afteradministration across dosing cohorts. The median maximum drugconcentration-time (T_(max)) was 1.0 hour or 1.5 hours. There werelittle differences in mean C_(max) or mean plasma AUC₂₄ among thecohorts. After Day 2, a maintenance dose of 80 to 160 mg was repeatedlyadministered once-daily. At Days 14 and 28, the plasma concentration ofunchanged Compound 1 rapidly increased after administration in allcohorts. The median T_(max) was 0.5-2.0 hours. The mean C_(max),C_(trough) and mean plasma AUC₂₄ generally increased proportionatelywith dose. At Day 28, the mean plasma T_(1/2) was 66.5-78.1 hours, andthere were little differences among the cohorts.

For Part B, a maintenance dose of 80 mg or 120 mg (starting with aloading dose of 320 mg on Day 1 for both cases) was repeatedlyadministered once-daily. The mean trough plasma concentration ofunchanged Compound 1 between Week 2 and Week 25 is shown in FIGS. 17Aand 17B. The median trough plasma concentration of unchanged Compound 1ranged between 2.60 ng/mL and 6.09 ng/mL in the 80 mg group (n=3-15) andbetween 5.72 ng/mL and 10.7 ng/mL in the 120 mg group (n=3-14) and weremaintained almost constant over time in both groups.

Example 7: A Double Blind, Randomized, Placebo-Controlled, Study toEvaluate the Effect of Compound 1 on Pharmacokinetics andPharmacodynamics in Healthy Men for Testosterone Lowering

Aim: To evaluate the PK, PD, safety and tolerability of Compound 1 inhealthy male subjects following single and once daily doses for 2 and 4weeks.

Key findings: PK was dosed proportionally over 80-360 mg range. The foodeffect with 180 mg dose was similar to that observed with 40 mg dose,demonstrating that the food effect is dose independent. The ANOVAresults showed that the C_(max) and AUC_(0-inf) ratios of least squaremeans (90% CI) of fed versus fasted state were 48.25 (22.62-102.90) and52.74 (29.99-92.76), respectively. A 360 mg single dose resulted incastrate levels (<50 ng/dL) within 24 hours post dose. 360 mg Day 1 and40 mg day 2 to 14 resulted in rapid castration level and sustainedcastration level. 320 mg day 1, 160 mg day 2, and 40 mg day 3 to 28 didnot maintain castrate level. 80 mg once daily took up to 21 days toreach castrate level.

This was a randomized, double-blind, placebo-controlled, single andmultiple dose, study in healthy men to evaluate the safety,tolerability, pharmacokinetics, and efficacy for testosterone loweringof Compound 1, an oral GnRH antagonist. The study had 4 parts: Part 1(inpatient) included single dose administration of the Compound 1formulation across 4 dose cohorts plus placebo and included a fed/fastedarm; Part 2 (inpatient) included multiple dose administration of theCompound 1 formulation for 14 days across 5 dose cohorts plus placebo;and Parts 3 and 4 (outpatient) included once-daily (QD), multiple doseadministration of the Compound 1 formulation for 28 days across 2 dosecohorts (total of 4 dose levels), plus placebo.

The Compound 1 formulation was supplied as light red-colored,film-coated tablets, each containing active Compound 1. The 120 mgCompound 1 formulation comprised a core tablet of Compound 1 (120 mg),mannitol (366 mg), microcrystalline cellulose (60 mg), hydroxypropylcellulose (18 mg), croscarmellose sodium (30 mg), and magnesium stearate(6 mg). The core tablets were coated with a film coating comprisinghypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg), and red ferricoxide (0.06 mg). The amounts of the excipients in the core tablet andfilm coating were adjusted accordingly based on the amount of Compound 1in the core tablet (e.g., for the 360 mg tablet, the amount of excipientadded to the core tablet and film coating is three times the amountadded to the 120 mg tablet).

In Part 1, a single oral dose of 80 mg, 120 mg, 180 mg, and 360 mgCompound 1 formulation was administered. In Part 2, 80 mg, 180 mg, 40mg, and 20 mg Compound 1 formulation was administered for 14 days. The40 mg dose was administered once per day with a single load dose of 360mg on Day 1 of the 14 days of treatment administration. For the 20 mgdosages, one 20 mg dose was administered with loading doses of 320 mg onDay 1, 240 mg on Day 2, and 160 mg on Day 3, and the other 20 mg dosewas administered with loading doses of 320 mg on Day 1 and 160 mg on Day2. Parts 3 and 4 of the study administered 40 mg or 160 mg, and 60 mg or80 mg Compound 1 formulation QD for 28 days, respectively. The 40 mgdose was administered with loading doses of 320 mg and 160 mg on Days 1and 2 of treatment, respectively.

Part 1 included single oral dose administration; Part 2 included 14 daysof daily treatment; and Parts 3 and 4 included 28 days of dailytreatment.

Blood (approximately 4 mL) and urine samples were collected for thedetermination of the plasma (Parts 1 through 4) and urine (Parts 1 and2) concentrations of Compound 1. Samples were analyzed using validatedliquid chromatography with tandem mass spectrometry (LC/MS/MS) methods.The LLOQ was 0.0100 ng/mL for plasma and 0.500 ng/mL for urine.

The main pharmacodynamic variables included serum concentrations of LHand testosterone, measured at regular intervals following single- andmultiple dose administration of the Compound 1 formulation in Parts 1through 4. FSH, DHT, and insulin-like growth factor 1 (IGF-1; Parts 3and 4 only) were measured in a subset of samples. Serum testosterone wasassayed using a conventional immunoassay for screening (LLOQ=0.4nmol/L). A validated LC/MS/MS method, with an LLOQ of 0.173 nmol/L and aULOQ of 10.425 nmol/L, was used for all subsequent baseline (i.e., thesubject's serum hormone levels prior to treatment commencing) andpostdose measurements.

Individual Compound 1 plasma and urine concentration-time data obtainedin Parts 1 and 2 were analyzed using noncompartmental methods (WinNonlinEnterprise version 5.2) to characterize the single- and multiple dosepharmacokinetics of the Compound 1 formulation and to evaluate theeffect of food on the Compound 1 formulation pharmacokinetics.Individual plasma and/or urine concentrations and single- and multipledose PK parameters of the Compound 1 formulation were listed andsummarized descriptively by study part, study day, and dose level.Dose-proportionality of PK parameters of the Compound 1 formulationafter single and multiple dosing were first explored graphically byplotting individual dose-normalized exposure parameters: dose-adjustedobserved mean C_(max)/D, dose-adjusted mean plasma AUC_(0-tlqc)/D anddose-adjusted mean plasma AUC_(0-tau)/D, or dose-adjusted over thedosing interval mean plasma AUC_(0-tau)/D versus dose. Then, a formalassessment was performed using both analysis of variance (ANOVA) andpower model approaches. In Part 1 (Cohort 3), ANOVA was performed onln-transformed PK parameters [mean plasma AUC_(0-tlqc), mean plasmaAUC_(0-∞), and mean C_(max)] of Compound 1 to assess the effect of foodon Compound 1 oral bioavailability. In Part 2, steady state attainmentwas determined based on visual inspection of mean observed predoseplasma concentration during multiple dosing (C_(trough)) versus timeprofiles at each dose level. Noncompartmental analysis of Part 3 and 4data were not planned given the limited number of postdose samplescollected per subject on Days 1 and 28.

Pharmacodynamic measures included serum concentrations of testosterone,DHT, LH, and FSH. In Part 2, the number and percentage of subjects withaverage serum testosterone levels less than 0.69 nmol/L occurring duringthe second week of dosing were tabulated. In Parts 3 and 4, the numberand percentage of subjects with serum testosterone levels consistentlyless than 0.69 nmol/L from Day 14 through Day 28 were tabulated.

In Part 1, single dose pharmacokinetics of Compound 1 were evaluated inhealthy male subjects at 4 dose levels (80, 120, 180, and 360 mg) underfasted conditions and at 1 dose level (180 mg) 30 minutes afteringestion of a standard, FDA-recommended, high fat, high-caloriebreakfast (fed conditions). Mean plasma concentration-time profiles ofCompound 1 are presented in FIGS. 18A, 18B, and 19. A summary ofrelevant plasma and urine PK parameters is in FIG. 20.

In Part 2, multiple dose pharmacokinetics of Compound 1 were evaluatedin healthy male subjects at 4 dose regimens (20, 40, 80, and 180 mg)given QD for 14 days; of these doses, 3 included a loading doseadministered during the first 1, 2, or 3 days. Mean Compound 1 plasmaconcentration-time profiles on Days 1 and 14 are presented graphicallyin FIGS. 21A and 21B. Summaries of all relevant plasma and urine PKparameters obtained on Days 1 and 14 are presented in FIGS. 22 and 23,respectively.

On Days 1 and 14, Compound 1 was administered to healthy, adult, malesubjects 30 minutes prior to the ingestion of a standardized morningmeal was readily absorbed in plasma. Observed peak concentrationstypically occurred within 1 to 2 hours after dosing. When comparing theabsorption profiles of a single 180 mg dose administered in the fastedstate (Part 1) or 30 minutes prior to ingestion of a standardized meal(Part 2, Day 1), it was noted that mean plasma AUC₀₋₂₄ decreased to alesser extent (approximately 28%) while no changes were observed in therate of absorption (mean C_(max) and T_(max)) of Compound 1.

Compound 1 was readily absorbed in plasma following single and multipleoral administration. The absorption phase was somewhat erratic, withindividual first time to T_(max) values ranging from 0.5 to 12 hourspostdose (median ˜2 hours) across all doses studied. Co-administrationwith food decreased mean C_(max) and mean plasma AUC_(0-∞) byapproximately 50% and delayed absorption (median T_(max) 5 hours) whencompared to fasting conditions. When dosing 30 minutes prior toingestion of a standardized meal, the rate of absorption was unchangedwhile the Compound 1 systemic exposure (mean plasma AUC) was reduced onaverage by approximately 28%.

The absorption of Compound 1 in plasma was decreased and delayedfollowing a single 180 mg dose administered 30 minutes after the startof a standard U.S. FDA high fat, high-calorie breakfast (approx.800-1000 calories, 50% from fat) compared to fasting conditions. MedianT_(max) increased from 1.75 to 5.00 hours under fed conditions. The meanC_(max) and mean plasma AUC_(∞) ratios (and associated 90% CI) of leastsquare means of fed versus fasted state were 48.25% (22.62%, 102.90%)and 52.74% (29.99%, 92.76%), respectively, indicating a clinicallymeaningful effect of food on the oral bioavailability of Compound 1. Inthe 14 day inpatient multiple dose Part 2, the Compound 1 formulationwas administered daily 30 minutes prior to ingestion of a standardizedmorning meal (approx. 600 calories, 27% from fat). Under theseconditions, systemic exposure to Compound 1 was reduced to a lesserextent (approximately 28% on average) and no obvious changes in the rateof absorption were observed when compared to fasting conditions.Consequently, in the 28 day outpatient multiple dose Parts 3 and 4,subjects were instructed to take the Compound 1 formulation upon arisingin the morning, on an empty stomach, and start eating approximately 30minutes after dosing whenever possible.

In general, approximate dose-proportional increases in mean C_(max) andmean plasma AUC_(0-∞) were observed after single doses of 80 mg to 360mg. At steady state, mean plasma AUC_(0-tau) increased in adose-proportional manner following multiple doses of Compound 1 over thedose range of 20 to 180 mg QD, while mean C_(max) increased slightlymore than dose-proportionately. It was noted that there was a moderateto large interindividual variability in the Compound 1 systemicexposures across all study parts.

After attaining mean C_(max), plasma Compound 1 concentrations declinedin a multi-exponential manner with a mean plasma T_(1/2) ranging from19.1 to 21.7 hours after single dosing and from 35.8 (180 mg QD) to 64.5hours (20 mg QD) after repeat dosing. Steady state was reached within 11to 14 days following the start of QD dosing. The observed accumulationfactor, based on mean plasma AUC_(0-tau), was 1.92 and 2.16 for the 80mg and 180 mg QD dose regimens, respectively.

Less than 4% of Compound 1 was excreted unchanged in urine after singleand repeat dosing. Mean renal clearance of Compound 1 represented asmall portion of its total clearance, thus indicating that renalexcretion plays a minor role in the elimination of Compound 1.

Clinically-relevant mean serum testosterone suppression was noted tohave occurred 4 to 6 hours following single doses of 80 mg, 120 mg, 180mg and 360 mg of Compound 1, and this was maintained through 36 hourspostdose. Mean serum LH concentration profiles were similar totestosterone for these 4 doses. Mean serum LH concentration-time data(IU/L) for the treatment period (Part 1) is presented in FIG. 24. Meantime-course of serum testosterone lowering following a single doseadministration of Compound 1 (Part 1) is shown graphically in FIG. 25.Mean serum testosterone concentration-time data (nmol/L) for thetreatment period (Part 1) is presented in FIG. 26.

Mean serum FSH concentration-time data (IU/L) for the treatment period(Part 1) is presented in FIG. 27. The mean serum FSH concentrationprofile was similar across respective dose cohorts at corresponding timepoints for the 80, 120, 180, and 360 mg groups. Mean serum FSHconcentrations began to decrease 2 hours postdose to a low at 48 hours.

Mean serum DHT concentration-time data (nmol/L) for the treatment period(Part 1) is resented in FIG. 28. The mean serum DHT concentrationprofile was similar across respective dose cohorts at corresponding timepoints for the 80, 120, 180, and 360 mg groups. Mean serum DHTconcentrations began to decrease 2 hours postdose. Decreases in DHT weremore profound in the 180 and 360 mg dose cohorts, with minor andvariable further reductions occurring after the 12 hour time point.

Following 14 days of daily dosing, mean serum LH and testosterone andconcentration profiles were similar for the 80 mg, 180 mg, and 40 mgCompound 1 dose cohorts. Concentrations decreased from 2 to 6 hourspostdose through Day 14. Either 1 to 3-day loading dose regimens ordoses of 180 mg QD resulted in rapid reductions in serum testosteroneconcentrations over the first 48 hours following start of dosing.However, the daily maintenance dose was a major determinant of sustainedserum testosterone suppression. The profound castration threshold(defined for this study as average serum testosterone levels <0.69nmol/L) was achieved with multiple dosing for 14 days at doses of 40,80, and 180 mg; however, 20 mg QD was insufficient in maintainingadequate suppression of serum LH and testosterone concentration levelsduring the second week.

There was no increase in the incidence of adverse events (AEs) wasobserved with increasing dose of Compound 1. The most common treatmentemergent adverse events (TEAEs) observed across all dose cohorts werebradycardia, hot flush, and headache. The most common drug-related TEAEwas hot flash. There were no deaths, serious adverse events (SAEs), orsevere AEs following single dose treatment or multiple dose treatmentwith the Compound 1 formulation for 14 or 28 days.

Safety results showed that single and multiple doses of the Compound 1formulation administered were safe and well tolerated.

Compound 1 was readily absorbed in plasma following single and multipledose oral administration. After attaining mean C_(max), typicallyoccurring within 1 to 2 hours after repeat dosing, plasma Compound 1concentrations declined in a multi-exponential manner with a meandisposition phase. Mean plasma T_(1/2) was approximately 36 to 65 hoursacross the 20 to 180 mg QD dose range. Moderate to large interindividualvariability in Compound 1 systemic exposures was apparent across allstudy parts.

At steady state, mean plasma AUC_(0-tau) increased in adose-proportional manner following multiple doses of Compound 1 over thedose range of 20 to 180 mg QD, while mean C_(max) increased slightlymore than dose-proportionately. Steady state conditions were reachedwithin 10 to 14 days and Compound 1 systemic exposure increasedapproximately 2 fold (200%) following QD dosing.

Co-administration with food decreased Compound 1 systemic exposure (meanC_(max) and mean plasma AUC_(0-∞)) by approximately 50% and delayedabsorption when compared to fasting conditions.

Effective medical castration was consistently achieved at maintenancedoses of 80 mg, 160 mg and 180 mg QD. Only load doses of 180 mg orgreater led to serum testosterone levels below the medical castrationlimit of 1.73 nmol/L within 24 to 48 hours. While a large variability inthe pharmacodynamics response was apparent across cohorts, higher dosesof Compound 1 produced more robust serum testosterone suppression. Therecommended safe and effective dose regimen based on this study would be≥80 mg QD Compound 1 for sustained castration during the treatmentperiod.

Consistent with the mechanism of action of GnRH antagonists, Compound 1caused an immediate and effective suppression of gonadotropins (LH, FSH)and serum testosterone as a result of competitive binding for thepituitary GnRH receptors.

Mean serum LH concentration-time data (IU/L) for the treatment period(Part 2) is presented in FIG. 29. Mean time-course of serum testosteronelowering following a multiple oral dose administration of Compound 1(Part 2) is depicted graphically in FIG. 30. Mean serum testosteroneconcentration-time data (nmol/L) for the treatment period (Part 2) istabulated in FIGS. 31A and 31B.

Mean serum FSH concentration-time data (IU/L) for the treatment period(Part 2) is presented in FIG. 32. Postdose mean serum FSH concentrationprofiles were similar across respective dose cohorts at correspondingtime points for the 80, 180, 40 and 20 mg groups, in which theydecreased from 24 hours postdose through Day 14 (end of dosing).

Mean serum DHT concentration-time data (nmol/L) for the treatment period(Part 2) is presented in FIG. 33. The mean serum DHT concentrationprofiles were generally consistent with serum testosterone.

Following administering of 80 mg and 180 mg of the Compound 1formulation for 16 days in Part 2, the change from baseline in meanserum LH concentration at the end of 16 days of treatment was 13.8 fold(1380%) reduction for 80 mg dosage (reduced from 4.57 IU/L to 0.33IU/L), and 17 fold (1700%) reduction for 180 mg dosage (reduced from3.90 IU/L to 0.23 IU/L).

Following administering for 16 days in Part 2, the change from baselinein mean serum testosterone concentration at the end of 16 days oftreatment is 29 fold (2900%) reduction for 80 mg dosage (reduced from10.40 nmol/L to 0.3565 nmol/L), and 24 fold (2400%) reduction for 180 mgdosage (reduced from 10.40 nmol/L to 0.4320 nmol/L).

Following administering for 16 days in Part 2, the change from baselinein mean serum FSH concentration at the end of 16 days is 9.1 fold (910%)reduction for 80 mg dosage (reduced from 6.07 IU/L to 0.67 IU/L), and11.8 fold (1180%) reduction for 180 mg dosage (reduced from 3.88 IU/L to0.33 IU/L).

Following administering for 16 days in Part 2, the change from baselinein mean serum dihydrotestosterone concentration at the end of 16 days is1.7 fold (170%) reduction for 80 mg dosage (reduced from 1.883 nmol/L to1.095 nmol/L), and 2.2 fold (220%) reduction for 180 mg dosage (reducedfrom 1.882 nmol/L to 0.865 nmol/L).

In healthy, older men in Parts 3 and 4 of the study, effective medicalcastration was consistently achieved over 14 and 28 days dosing at dailydoses of 40 mg to 180 mg (14 days) and 80 mg to 160 mg (28 days). Use ofa load dose for up to 3 days (or daily doses of 160 mg or higher)resulted in below castration levels of serum testosterone (50 ng/dL or1.73 nmol/L) within 24 to 48 hours.

Mean serum LH concentration-time data (IU/L) for the treatment period(Part 3) is presented in FIG. 34, and for the treatment period (Part 4)is presented in FIG. 39. Mean time-course of serum testosterone loweringfollowing a multiple oral dose administration of Compound 1 (Part 3) isshown in FIG. 35, and administration of Compound 1 (Part 4) is shown inFIG. 40. Mean serum testosterone concentration-time data (nmol/L) forthe treatment period (Part 3) is presented in FIG. 36, and for thetreatment period (Part 4) is presented in FIG. 41.

Mean serum FSH concentration-time data (IU/L) for the treatment period(Part 3) is presented in FIG. 37, and for the treatment period (Part 4)is presented in FIG. 42.

Mean serum DHT concentration-time data (nmol/L) for the treatment period(Part 3) is presented in FIG. 38, and for the treatment period (Part 4)is presented in FIG. 43.

In dosing for 28 days, both 160 mg (Part 3) and 80 mg (Part 4) wereeffective at achieving medical (<1.73 nmol/L) and profound (<0.69nmol/L) castration during the third and fourth weeks of repeatadministration. However, the 40 mg QD dose was ineffective inmaintaining castration between Days 14 and 28. The results at 60 mg QDwere intermediate to those of 40 and 80 mg and suggested that the likelyminimal, fully effective maintenance dose for medical castration wouldbe at 80 mg QD or above.

Consistent with the observed dose-dependent suppression of serumtestosterone across the 20 to 180 mg QD studied dose range, themagnitude of the serum testosterone lowering-response was correlatedwith individual Compound 1 plasma trough concentrations; the higher theCompound 1 systemic exposure, the greater the number of subjectsachieving and maintaining medical castration throughout the treatmentperiod. Median Compound 1 trough concentrations of greater than 4 ng/mL,which were associated with maintenance doses of 80 mg or greater,reduced serum testosterone to below medical castration levels of 1.73nmol/L in all subjects with the majority having serum testosteronelevels decreased to below the profound castration threshold of 0.69nmol/L after 28 days of treatment with the Compound 1 formulation.

The time-course of serum testosterone suppression following treatment(Part 2) with Compound 1 in healthy men for 14 days is shown in FIG.44A-44D. The correlation between serum testosterone suppression andCompound 1 steady state exposure in healthy men (Part 2) is shown isFIG. 45, and in healthy men (Parts 3 and 4) is shown is FIG. 48. Thetime-course of serum testosterone suppression following treatment (Parts3 and 4) with Compound 1 in healthy men for 28 days is shown in FIG.46A-46D. The percent of subjects reaching serum testosterone belowcastration levels after 28 days of treatment (Parts 3 and 4) withCompound 1 is shown in FIGS. 47A and 47B.

Compound 1 was well tolerated, with no AEs of symptomatic significanceunless directly related to the effects of acute medical castration. Mildto moderate transaminase elevations were observed without symptoms orchanges in total bilirubin. Changes in QT/QTc intervals were consistentwith those described in the literature with other medical castrationagents.

Example 8: A Study to Evaluate the Effect of Compound 1 in Men withAdvanced Prostate Cancer for Testosterone Lowering and PSA Response

In this study, patients with advanced prostate cancer who requirefirst-line androgen deprivation therapy (ADT) received either 80 mg or120 mg daily of oral Compound 1 formulation (with a load dose of 320 mgon Day 1) or leuprolide acetate 22.5 mg SC. The 120 mg Compound 1formulation comprised a core tablet of Compound 1 (120 mg), mannitol(366 mg), microcrystalline cellulose (60 mg), hydroxypropyl cellulose(18 mg), croscarmellose sodium (30 mg), and magnesium stearate (6 mg).The core tablets were coated with a film coating comprising hypromellose2910 (21.36 mg), titanium dioxide (2.4 mg), and red ferric oxide (0.06mg). The amounts of the excipients in the core tablet and film coatingwere adjusted accordingly based on the amount of Compound 1 in the coretablet (e.g., for a 360 mg tablet, the amount of excipient added to thecore tablet and film coating is three times the amount added to the 120mg tablet).

The Compound 1 formulation or conventional leuprolide acetate wasadministered for up to 48 weeks. For treatment with Compound 1, studyvisits occurred at baseline (week 1), day 1 of weeks 2, 3, and 5, andthen every 4 weeks until week 49 (the end of the 48-week core studyperiod). All patients who completed ≥12 weeks of Compound 1 therapy werefollowed off-treatment for 12 weeks with assessments at 4 (end oftreatment, EOT), 8 (follow-up visit), and 12 (end of study, EOS) weeks.For patients receiving leuprolide acetate (leuprorelin), on-treatmentstudy visits occurred at baseline (day 1, week 1), day 1 of weeks 2, 3,and 5, and then every 4 weeks until week 25, and then at 12 weekintervals (week 37 and 49). Patients on leuprorelin received their finalinjection at week 37, day 1, and the week 49, day 1 visit was consideredthe end of leuprorelin exposure. Patients receiving leuprorelin atvisits at 16 (EOT), 20 (follow-up visit), and 24 (EOS) weeks after thelast leuprorelin injection.

Eligible men were aged ≥18 years with a histologically confirmeddiagnosis of prostate adenocarcinoma, and were candidates for ADT forthe management of hormone-sensitive prostate cancer with one of thefollowing clinical disease states: advanced localized disease notsuitable for primary surgical or radiation therapy; evidence of PSAbiochemical or clinical relapse following primary surgery or radiationtherapy of curative intent; or newly diagnosed metastatic disease thatwas asymptomatic and without visceral involvement. Additional inclusioncriteria at screening included: eugonadal serum testosterone >150 ng/dL(5.2 nmol/L); serum PSA concentration >2 ng/mL (or, whenapplicable, >0.2 ng/mL following radical prostatectomy or >2 ng/mL abovethe post-radiotherapy nadir following radiotherapy); body mass index≥18.0 at screening and/or baseline (i.e., the subject's BMI prior totreatment commencing); and Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1. Patients with advanced, localized M0N1 orM1 disease with clinically significant symptoms or visceral involvement,who required immediate GnRH therapy, chemotherapy, or radiation therapywere not eligible for the trial.

The time-course and intensity of serum testosterone lowering observed inpatients in this study receiving the Compound 1 formulation was similarto that observed in the study in healthy older men in Example 7. Serumtestosterone levels were measured at each visit. On average, in patientsreceiving the Compound 1 formulation, serum testosterone decreased tobelow the medical castration threshold of 50 ng/dL (1.73 nmol/L) by Day4 (end of Day 3) visit, and to below the profound castration thresholdof 20 ng/dL (0.69 nmol/L) by the Week 5 Day 1 visit. In contrast, inpatients receiving leuprolide acetate, serum testosterone levels roseduring the first 1-2 weeks of therapy then declined to castration levelsby Week 5 Day 1. In the Compound 1 groups, median serum testosterone wassuppressed below the profound castration threshold (<20 ng/dL) fromweeks 5-49. The most common adverse event was hot flush in 31 (55%), 35(65%), and 15 (63%) patients in the Compound 1 80 mg, Compound 1 120 mg,leuprorelin groups, respectively.

Quality of life (QoL) was assessed throughout the study and thefollow-up period. The 25-item Prostate Cancer Module of the EuropeanOrganization for Research and Treatment of Cancer Quality of LifeQuestionnaire (EORTC QLQ-PR25), Aging Male Survey (AMS), and core30-item EORTC Quality of Life Questionnaire (EORTC QLQ-C30) werecompleted at screening, day 1 of weeks 5, 13, 25, 37, and 49, and, ifapplicable, at the follow-up visits.

PSA levels were measured at each visit. On average, in patientsreceiving the Compound 1 formulation, PSA levels decreased to less than0.4 ng/mL by the Week 13 Day 1 visit and to less than 0.2 ng/mL by theWeek 21 Day 1 visit. Following initiation of treatment, the PSA responsewas more rapid in patients receiving Compound 1 compared withleuprorelin (FIG. 52). Patients receiving Compound 1 also achieved PSAnadir more quickly than patients receiving leuprolide acetate (Table 1).Eighty-three percent of patients receiving Compound 1 had a ≥50% serumPSA reduction after 4 weeks of treatment versus only 20% of patientsreceiving leuprolide. Eight percent of patients receiving Compound 1 hada ≥90% serum PSA reduction after 4 weeks of treatment versus 0% ofpatients receiving leuprolide.

TABLE 1 Median Time from First Dose to PSA Nadir Compound 1 Compound 1Leuprolide 80 mg QD 120 mg QD Q12W (N = 56) (N = 54) (N = 24) Mediantime from 16.1 12.3 20.5 first dose to PSA (1.60-24.70) (2.00-24.60)(8.00-24.60) nadir Weeks (range)

FSH levels were also measured at each visit. Compound 1 caused greatersuppression of FSH compared to leuprorelin (leuprolide acetate). Thiswas seen at both the 80 mg and 120 mg doses of Compound 1 (Table 2).Median FSH was ˜4.2 mIU/mL with leuprolide (agonist) after 48 weeks oftreatment. Although FSH did drop with leuprolide, it was not sustainedsuppression. However, with Compound 1 (antagonist), median FSH was 1.62mIU/mL after 48 weeks of treatment, and this was far more sustained overthe 48 weeks. FSH dropped from >10 mIU/mL at baseline to the 0.6-1.6mIU/mL range for Compound 1, 120 mg dose over the course of 48 weeks.

TABLE 2 FSH Levels (IU/L) over Time Compound 1 Leuprorelin 80 mg QD 120mg QD Total Q12W (N = 56) (N = 54) (N = 110) (N = 24) n (%) n (%) n (%)n (%) Baseline (b) n 56 54 110 24 Mean (Std Dev) 14.729 (14.3473) 15.830(12.8724) 15.269 (13.5920) 19.688 (19.1894) Median 9.550 11.050 9.85014.500 Min, Max 2.80, 77.60  2.80, 68.60 2.80, 77.60 2.00, 79.40 Week 2,Day 1 n 52 52 104 22 Mean (Std Dev) 3.112 (3.0612) 3.183 (2.8956) 3.147(2.9653) 7.650 (5.4542) Median 2.100 2.300 2.150 5.150 Min, Max 0.30,13.90  0.30, 16.10 0.30, 16.10 0.60, 18.80 Week 5, Day 1 n 54 52 106 24Mean (Std Dev) 1.248 (2.6757) 1.035 (1.0479) 1.143 (2.0379) 2.946(1.4428) Median 0.400 0.600 0.550 2.550 Min, Max 0.30, 17.40 0.30, 5.700.30, 17.40 0.90, 6.30  Week 13, Day 1 n 52 50 102 24 Mean (Std Dev)1.137 (2.4242) 0.908 (0.8104) 1.025 (1.8164) 4.625 (2.5594) Median 0.5000.600 0.500 3.600 Min, Max 0.30, 16.90 0.30, 3.10 0.30, 16.90 0.40,11.50 Week 25, Day 1 n 49 48 97 23 Mean (Std Dev) 1.090 (0.9932) 1.344(0.9675) 1.215 (0.9838) 5.043 (2.8221) Median 0.800 1.200 0.900 4.400Min, Max 0.30, 6.10  0.30, 4.00 0.30, 6.10  1.90, 14.50 Week 49, Day 1 n46 42 88 20 Mean (Std Dev) 1.802 (1.3956) 1.938 (1.2169) 1.867 (1.3077)5.145 (2.8201) Median 1.450 1.600 1.500 4.250 Min, Max 0.30, 8.00  0.30,4.60 0.30, 8.00  2.10, 10.70 LLQ = lower limit of quantification, Max =maximum, Min = minimum, Q12W = once every 12 weeks, QD = once daily, StdDev = standard deviation. (a) Baseline was defined as the valuecollected at the time closest to, but prior to, the start of study drugadministration. The value <0.1 mlU/mL (LLQ) was imputed as 0.1 mlU/mL.(b) Baseline was defined as the value collected at the time closest to,but prior to, the start of study drug administration. The value <0.3IU/L (LLQ) was imputed as 0.3 IU/L.

Results of this study indicated that the time-course and intensity ofserum testosterone lowering observed in patients receiving the Compound1 formulation was similar to that observed during the study in healthyolder men in Example 7. On average, in patients receiving the Compound 1formulation, serum testosterone decreased to below the medicalcastration threshold of 50 ng/dL (1.7 nmol/L) by Day 4 (end of Day 3)visit, and to below the profound castration threshold of 20 ng/dL (0.7nmol/L) by the Week 5 Day 1 visit. In contrast, in patients receivingleuprolide acetate, serum testosterone levels rose during the first 1 to2 weeks of therapy then declined to castrate levels by Week 5 Day 1. Noserum testosterone surge or resultant tumor flare occurred afterCompound 1 treatment initiation. The more rapid reduction in PSA overthe first 2 weeks with Compound 1 administration, compared with thedelayed PSA response with leuprorelin, illustrates the rapid onset ofaction and therapeutic effect of Compound 1-mediated GnRH antagonism.Available data at the end of 24 weeks dosing showed that PSA % responsesexceed 90% in most patients.

The median serum testosterone levels at EOT (4 weeks after the end oftreatment) were 72.9 ng/dL for 120 mg Compound 1 versus 9.8 ng/dL withleuprorelin (Tables 3 and 4). At the follow-up visit, 8 weeks afterstopping treatment, the median serum testosterone levels were 329.8ng/dL for 120 mg Compound 1 versus 9.8 ng/dL with leuprorelin. At EOS,12 weeks after stopping treatment, the median serum testosterone levelswere 322.8 ng/dL for 120 mg Compound 1 versus 13.5 ng/dL withleuprorelin. The serum testosterone levels after stopping treatment withCompound 1 were above medical castration levels (50 ng/dL or 1.7 nmol/L)after 4 weeks after the end of treatment.

TABLE 3 Testosterone Levels During Follow-Up Visits Median testosterone,Compound 1 Leuprorelin ng/dL (range) n 80 mg QD n 120 mg QD n Q12W EOT14  90-0 (10.9-929.4) 21 72.9 (4.3-362.9) 18 9.8 (3.5-108.0) Follow-upvisit 8 379.7 (17.9-460.7) 11 329.8 (21.9-646.6) 15 9.8 (4.3-265.0) DOS15 153-8 (2.9-490.8)  15 322.8 (3.7-602.5)  14 13.5 (4.3-332.9)  D =day. EOS = end of study. EOT = end of treatment, Q12W = once every 12weeks. QD = once daily.

TABLE 4 Testosterone Values (nmol/L) During Follow-Up Compound 1Leuprorelin 80 mg QD 120 mg QD Total Q12W (N = 56) (N = 54) (N = 110) (N= 24) n (%) n (%) n (%) n (%) Baseline(a) n 55 54 109 24 Mean (Std Dev)13.755 (4.7256) 15.139 (5.4871) 14.441 (5.1404) 11.363 (5.0204) Median12.700 14.350 13.600 11.120 Min, Max 5.03, 27.20 4.51, 27.03 4.51, 27.20 4.30, 24.01 Week 49, Day 1 n 44 38 82 20 Mean (Std Dev) 0.526 (0.4621)0.443 (0.2745) 0.487 (0.3867) 0.478 (0.6313) Median 0.380 0.365 0.3800.300 Min, Max 0.11, 2.08  0.10, 1.42  0.10, 2.08  0.10, 3.05 End ofTreatment n 14 21 35 18 Mean (Std Dev) 7.211 (9.2178) 3.592 (3.7809)5.039 (6.6432) 0.641 (0.9616) Median 3.125 2.530 2.530 0.340 Min, Max0.38, 32.27 0.15, 12.60 0.15, 32.27 0.12, 3.75 Follow-Up n 8 11 19 15Mean (Std Dev) 11.004 (5.9971) 12.886 (6.1331) 12.094 (5.9829) 0.992(2.2948) Median 13.185 11.450 11.970 0.340 Min, Max 0.62, 16.69 0.76,22.45 0.62, 22.45 0.15, 9.20 End of Study n 15 15 30 14 Mean (Std Dev)6.933 (6.4298) 9.565 (7.6479) 8.249 (7.0702) 1.695 (3.0345) Median 5.34011.210 7.425 0.470 Min, Max 0.10, 17.04 0.13, 20.92 0.10, 20.92  0.15,11.56 LLQ = lower limit of quantitation, Max = maximum, Min = minimum,Q12W = once every 12 weeks, QD = once daily, Std Dev = standarddeviation. (a)Baseline was defined as the value collected at the timeclosest to, but prior to, the start of study drug administration. Thevalue <0.10 nmol/L (LLQ) was imputed as 0.10 nmol/L.

In patients with 12 week recovery data following discontinuation of 48weeks of Compound 1 treatment, consistent with testosterone recoverydata, QoL, such as AMS (Tables 5 and 6, lower AMS score is better) andsexual activity scores from the EORTC QLQ-PR25 appeared to improve morein the Compound 1 group than the leuprorelin group.

TABLE 5 AMS Total Score-During Treatment Compound 1 80 mg QD 120 mg QDLeuprorelin Q12W Mean (95% Cl) (N = 56) (N = 54) (N = 24) AMS totalscore Baseline* 55 29.8 (27.1-32.6) 53 29.9 (27.6-32.3) 24 28.3(24.2-32.3) Percent change from baseline W5, D1 54  3.9 (−2.6-10.6) 5210.9 (2.8-19.1)  24 10.1 (−1.4-21.6) W13, D1 52 14.8 (8.1-21.6)  51 17.3(7.7-26.8)  24 21.9 (6.5-37.3)  W25, D1 49 20.3 (10.1-30.4) 48 20.4(10.4-30.3) 23 47.0 (23.1-70.9) W37, D1 47 24.1 (14.2-34.1) 46 24.5(13.9-35.1) 22 49.4 (22.3-76.5) W49, D1 46 30.1 (16.8-41.4) 41 24.4(13.8-35.0) 21 60.0 (32.5-87.4)

TABLE 6 AMS Total Score-After Treatment Compound 1 Leuprorelin Mean 80mg QD 120 mg QD Q12W (95% CI) (N = 56) (N = 54) (N = 24) EOT** 13 30.5(−2.4-63.3) 16 39.2 (21.8-56.5) 13 61.0 (22.7-99.2) Follow-up 5 31.8(−10.2-73.9) 8 25.2 (−12.2-62.5) 14 53.8 (18.2-89.4) EOS 14 21.9(8.9-34.9) 12 25.3 (−6.1-56.7) 16 49.9 (21.0-78.7)AMS=aging male survey. CI=confidence interval. D=day. EOS=end of study.EOT=end of treatment. Q12W=once every 12 weeks. QD=once daily. Datapresented as mean (95% CI) change from baseline and percent change frombaseline at specified timepoints for AMS scores. For AMS total baselinescores, a high number indicates worsening or increased number ofsymptoms. *Baseline was defined as the value collected at the timeclosest to, but prior to, the start of study drug administration. **EOT,Follow-up and EOS quality-of-life scores include only the patients whodid not enter the extension phase or who did not start alternative orcontinued ADT after the W49D1 study visit.

Efficacy and safety analyses were conducted using a safety population(received ≥1 dose of study drug). The safety population included 56, 54,and 24 patients in the Compound 1 80 mg, Compound 1 120 mg, andleuprorelin groups, respectively. Safety was assessed by recording theincidence, severity, and types of treatment-emergent adverse events; byphysical examination (including slit lamp examination of the anterioreye); and by evaluating changes from baseline in weight, vital signs,12-lead electrocardiogram (ECG), and clinical laboratory parameters. Alladverse events and serious adverse events were recorded throughout theentire study period and for 30 days after the last dose of Compound 1 orfor 12 weeks plus 30 days after the last leuprorelin injection. Adverseevents were coded using the Medical Dictionary for Regulatory Activitiesversion 19.0 and graded according to National Cancer Institute CommonTerminology Criteria version 4.03 (Tables 7 and 8). Safety-relatedhaematology, chemistry, and urinalysis measurements were taken at eachstudy visit and analysed at a central laboratory (LabCorp).Phospholipidosis was assessed as part of the safety assessments. Theoverall safety profile of Compound 1 appeared similar to that seen inthe smaller observational leuprorelin cohort and did not suggest‘off-target’ or non-ADT-related side effects that might impact eitherpatient compliance or long-term maintenance. Intensive ophthalmologicevaluation of Compound 1-treated patients was performed to assess forthe presence of phospholipidosis, an adverse effect of Compound 1treatment observed in rats in non-clinical toxicity studies. Althoughcataracts appeared in the Compound 1 groups, only Compound 1-treated andnot leuprorelin-treated patients underwent comprehensive eyeexaminations, which included slit-lamp evaluations. A small increase inmean corrected QT interval, of unknown clinical significance, occurredin all treatment arms, confirming prior observations in patientsreceiving ADT.

TABLE 7 Summary of Treatment-Emergent Adverse Events (Safety Population)and Most Frequently Reported (≥10%) Adverse Events Compound 1 Compound 1Leuprorelin 80 mg QD 120 mg QD Q12W n (%) (N = 56) (N = 54) (N = 24) Anyadverse event 53 (95) 50 (93) 23 (96) Grade ≥3 adverse event 5 (9) 4 (7)2 (8) Drug-related adverse event 44 (79) 45 (83) 18 (75) Serious adverseevent  6 (11) 1 (2) 2 (8) Adverse event resulting in 2 (4) 2 (4) 0 studydrug discontinuation Death 1 (2) 0 (0) 1 (4) Most frequent adverseevents, n (%) Grade ≤2 Grade ≥3 Grade ≤2 Grade ≥3 Grade ≤2 Grade ≥3Patients with any cause 48 (86) 5 (9) 46 (85) 4 (7) 21 (88) 2 (8)adverse event Hot flush 31 (55) 0 35 (65) 0 15 (63) 0 Fatigue 11 (20) 0(0) 17 (32) 0  7 (29) 0 Cataract^(‡) 5 (9) 0 11 (20) 0 NA NA IncreasedALT 5 (9) 1 (2) 3 (6) 0  4 (17) 0 Arthralgia 5 (9) 0 3 (6) 1 (2) 1 (4) 0ALT = alanine aminotransferase. NA = not available. Q12W = once every 12weeks. QD = once daily. A treatment-emergent adverse event was definedas any adverse event that occurred after administration of the firstdose of treatment drug and through 30 days after the last dose ofCompound 1, or 12 weeks plus 30 days following the last dose ofleuprorelin. The percentage is based on the total number of patients inthe safety population of the 48-week core period. ^(‡)Ophthalmologyexaminations were performed only in patients treated with Compound 1.

TABLE 8 Overall Grade ≥3 Adverse Events in the 48-week Treatment PeriodCompound 1 Leuprorelin 80 mg QD 120 mg QD Q12W n (%) (N = 56) (N = 54)(N = 24) Patients with at 9 (16) 8 (15) 2 (8) least 1 Grade ≥3 adverseevents Alanine 2 (4) 0 0 aminotransferase increased Aspartate 2 (4) 0 0aminotransferase increased Death 0 1 (2) 0 Sudden death 0 1 (2) 0 Acutecoronary 0 1 (2) 0 syndrome Arthralgia 0 1 (2) 0 Atrial flutter 0 1 (2)0 Bladder cancer 1 (2) 0 0 Cerebral haemorrhage 1 (2) 0 0Cerebrovascular 1 (2) 0 0 accident Cervical vertebral 1 (2) 0 0 fractureFatigue 1 (2) 0 0 Gamma- 1 (2) 0 0 glutamyltransferase increasedHypercalcaemia 0 1 (2) 0 Hypertension 0 1 (2) 0 Hypotension 1 (2) 0 0Inguinal hernia 0 1 (2) 0 Joint dislocation 1 (2) 0 0 Metastases to bone1 (2) 0 0 Musculoskeletal pain 0 1 (2) 0 Non-cardiac chest 0 1 (2) 0pain Osteoarthritis 0 1 (2) 0 Procedural pain 0 1 (2) 0 Sepsis 1 (2) 0 0Syncope 0 1 (2) 0 Transient ischaemic 1 (2) 0 0 attack Urinary tractinfection 1 (2) 0 0 Diabetes mellitus 0 0 1 (4) Myocardial infarction 00 1 (4)

Example 9: A Study to Evaluate the Effect of Compound 1 in Men withProstate Cancer Requiring ADT as Neoadjuvant and Adjuvant to ExternalBeam Radiation Treatment

External beam radiotherapy (EBRT) is a standard treatment option forintermediate/high-risk prostate cancer. The addition of androgendeprivation therapy (ADT) as an adjuvant/neoadjuvant, such asgonadotrophin-releasing hormone (GnRH) analogs, to EBRT has demonstratedprolonged overall survival. This study investigated the efficacy andsafety of the oral formulations comprising Compound 1, or apharmaceutically acceptable salt thereof.

Eligible male patients were aged ≥18 years with a histologicallyconfirmed diagnosis of localized, intermediate-risk prostate cancer, forwhom 6-month neoadjuvant and adjuvant androgen deprivation therapy (ADT)to external beam radiation therapy (EBRT) was indicated. The criteriafor establishing intermediate-risk prostate cancer included the presenceof one of the following, without any high-risk feature: T2b-T2c disease,Gleason score 7, or prostate-specific antigen (PSA) 10-20 ng/mL.Additional inclusion criteria included: EBRT scheduled to begin ≥12weeks after baseline visit; screening serum testosterone >150 ng/dL (5.2nmol/L); screening PSA concentration >2 ng/mL; body mass index ≥18.0 atscreening or baseline (i.e., the subject's BMI prior to treatmentcommencing); Eastern Cooperative Oncology Group performance status of 0or 1 at screening. Based on investigator discretion and clinicalassessment of the patient's overall medical and disease status,participation was allowed for older patients with high-risk disease(e.g., based on Gleason score or tumor status) who were deemed likely tobenefit from 6 months of neoadjuvant/adjuvant ADT. Most patients hadintermediate-risk disease. However, a few patients, based on Gleasonscore or tumor, node, and metastasis staging system, were technically ofhigher than intermediate risk.

Patients with prior or current use of a gonadotropin-releasing hormoneanalog or androgen receptor antagonist as first-line hormone therapy(unless total treatment duration was <6 months and was completed ≥1 yearprior to planned baseline visit), history of another malignancy in the 2years prior to first dose of study drug, or previous malignancy withevidence of residual disease, were excluded. Additional exclusioncriteria included presence of a clinically significant underlyingdisease.

In this study, patients received oral Compound 1 formulation 120 mg QD(with 320 mg load dose on Day 1) or degarelix 80 mg SC once every 4weeks (Q4W) (with 240 mg load dose on Day 1). Both treatment armsreceived treatment for 24 weeks. Patients remained on treatment for atleast 12 weeks before the start of external beam radiation treatment(EBRT), which was initiated for most patients between Week 13, Day 1 andWeek 15, Day 1. EBRT began no later than day 1, week 17.

The 120 mg Compound 1 formulation comprised a core tablet of Compound 1(120 mg), mannitol (366 mg), microcrystalline cellulose (60 mg),hydroxypropyl cellulose (18 mg), croscarmellose sodium (30 mg), andmagnesium stearate (6 mg). The core tablets were coated with a filmcoating comprising hypromellose 2910 (21.36 mg), titanium dioxide (2.4mg), and red ferric oxide (0.06 mg). The amounts of the excipients inthe core tablet and film coating were adjusted accordingly based on theamount of Compound 1 in the core tablet (e.g., for the 360 mg tablet,the amount of excipient added to the core tablet and film coating isthree times the amount added to the 120 mg tablet).

Patients were evaluated every 4 weeks during the treatment period(including day 1, week 25), at end of treatment (defined as week 29),during follow-up (week 33), and at end of study (EOS). The EOS visit wasdefined as week 37, or 12 (Compound 1) or 16 (degarelix) weeks after thelast dose of study drug, whichever was soonest.

Samples for testosterone, luteinizing hormone (LH), FSH, and PSAconcentrations were taken at screening, on day 1 of the first week(additionally days 2 and 4 for testosterone and LH), and on day 1 ofweeks 2, 3, 5, 9, 13, 17, 21, 25, 29, 33, and 37 thereafter. On average,in patients receiving the Compound 1 formulation, PSA levels decreasedto <0.2 ng/mL by the Week 13 Day 1 visit. By Day 4, LH levels were lowfor both the Compound 1 and degarelix treated groups (Compound 1: 0.462mIU/mL; degarelix: 0.499 mIU/mL). FSH levels at this time point were notavailable; however, a decrease from the levels before administration ofCompound 1 or degarelix (Compound 1: 11.826 IU/L; degarelix: 11.716IU/L) was noted at Week 2, Day 1 (Compound 1: 2.363 IU/L; degarelix:2.519 IU/L) for both groups. Suppression of FSH was less profound thanthat of LH, but consistent with the literature, and was greater thanthat observed with GnRH agonists. Mean levels of LH and FSH remained lowthrough the Week 25, Day 1 Visit for both groups (Compound 1, LH: 0.325IU/L; degarelix, LH: 0.342 IU/L; Compound 1, FSH: 1.475 IU/L; degarelix,FSH: 1.471 IU/L).

Quality of Life (QoL) was assessed via the core 30-item EuropeanOrganisation for Research and Treatment of Cancer quality of lifequestionnaire (EORTC QLQ-C30), the 25-item prostate cancer module EORTCquestionnaire (EORTC QLQ-PR25), and the aging male survey (AMS). QoLassessments were completed at screening, on day 1 of weeks 1, 5, 13, and25, and at weeks 29, 33, and 37.

The time-course and intensity of serum testosterone lowering observed inpatients in this study receiving the Compound 1 formulation was similarto that observed during the study in healthy older men in Example 7 andduring the study in patients with prostate cancer in Example 8. Serumtestosterone levels were measured at each visit. On average, in patientsreceiving the Compound 1 formulation, serum testosterone decreased tobelow the medical castration threshold of 50 ng/dL (1.73 nmol/L) by Day4 (end of Day 3) visit, and to below the profound castration thresholdof 20 ng/dL (0.69 nmol/L) by the Week 5 Day 1 visit.

For this study, serum testosterone lowering over Day 1 through Day 15showed a rapid reduction over the first 24 hours and on average belowmedical castration levels of serum testosterone 72 hours (Week 1 Day 4)following start of dosing (or loading dose injection). The serumtestosterone lowering effect of Compound 1 120 mg daily over 25 weekswas as sustained as that with the degarelix injectable antagonistanalog. At the end of 8 weeks of dosing (before the start of radiationtherapy), in patients with hormone-sensitive cancer in whom the prostategland and tumor remain in situ, PSA % responses were less than observedin the study in Example 8, but nonetheless exceed 89% in most patients.The PSA responses in both the Compound 1 formulation and degarelixtreatment groups appear similar. The proportion of patients achievingPSA values less than 0.2 ng/mL by the end of 12 weeks was 6 of 30patients for the Compound 1 formulation arm versus 1 of 20 patients forthe degarelix arm.

Rates for medical castration (less than 50 ng/dL) and profoundcastration (less than 20 ng/dL) were determined over the course of 24weeks overall, for subjects who received at least 12 weeks of treatment,and for subjects who received at least 24 weeks of treatment. Overall,both medical castration and profound castration rates over 24 weeks werehigher for Compound 1 (95% and 82%, respectively) compared with thedegarelix group (89% and 68%, respectively), as shown in FIG. 49. Insubjects who had at least 12 weeks of treatment, castration rates weresimilar overall. In subjects who had at least 24 weeks of treatment, thetrend of higher castration rates with Compound 1 treatment (98% and 84%for medical castration and profound castration, respectively) comparedto degarelix (86% and 71% for medical castration and profoundcastration, respectively) continued as shown in FIG. 49.

Time to achieve medical castration level serum testosterone (less than50 ng/dL [1.73 nmol/L] and less than 20 ng/dL [0.69 nmol/L) and theestimated time to serum testosterone recovery (including estimatedpercentage of patients who had recovered to baseline value and thepercentage who recovered to greater than 280 ng/dL during 12 weeks offtreatment) were determined.

The time to castration appeared to be similar between treatment groups.Median time to medical castration (≤50 ng/dL) was 4 days (95% CI: 2-4)for the Compound 1 group and 3 days (95% CI: 2-4) for the degarelixgroup. Median time to profound castration (≤20 ng/dL) was 15 days (95%CI: 8-15) for the Compound 1 group and 12 days (95% CI: 8-15) for thedegarelix group.

After removal of therapy, mean serum testosterone levels in thedegarelix group remained low through the end of study. For the Compound1 group, serum testosterone levels increased to approximately 10 nmol/Lat the follow-up visit and at end of study (1.7 nmol/L is the medicalcastration level). As depicted in FIG. 50, time to serum testosteronerecovery to baseline levels or greater than 280 ng/dL was more rapid forCompound 1 compared with the degarelix group. Twelve weeks aftertreatment, approximately 43% of subjects achieve pre-treatment serumtestosterone levels or a serum testosterone level at or above 280 ng/dLby 12 weeks versus only 5.3% with degarelix (Table 9). Results weresimilar for patients who received at least 12 weeks or 24 weeks oftreatment. Based on achievement of baseline serum testosterone levels orgreater than 280 ng/dL for serum testosterone concentrations, theCompound 1 group showed quicker achievement of these levels compared tothe degarelix group (FIG. 53).

TABLE 9 Testosterone Values and Time to Testosterone Recovery (BaselineLevels or >280 ng/dL [9.72 nmol/L]) for Overall Safety PopulationCompound 1 Degarelix 120 mg QD 80 mg Q4W (N = 65) (N = 38) Baseline^(b)n 65 38 Mean (Std Dev) 14.067 (6.7100) 14.567 (5.5680) Median 12.35014.020 Min, Max 5.17, 44.76  4.79, 32.55 Week 25, Day 1 n 64 37 Mean(Std Dev) 0.395 (0.5584) 0.582 (1.5107) Median 0.280 0.310 Min, Max0.11, 4.34  0.10, 9.47 EOT n 61 38 Mean (Std Dev) 5.117 (5.7671) 0.576(1.2218) Median 3.260 0.335 Min, Max 0.10, 28.42 0.10, 7.81 Follow-up n62 37 Mean (Std Dev) 9.889 (6.3879) 1.206 (1.9330) Median 8.275 0.560Min, Max 0.35, 32.24 0.11, 9.13 EOS n 61 38 Mean (Std Dev) 9.661(5.4611) 3.038 (4.0224) Median 8.920 1.040 Min, Max 0.33, 29.81  0.13,13.15 Time to testosterone recovery (days) Number with events, n 34 (52)6 (16) (%) Number censored, n (%) 30 (46) 32 (84) 25^(th) percentile 57(45, 62) 100 (87, 106) (95% CI) Median (95% CI) 91 (62, 127) 100 (100,106) 75^(th) percentile 127 (93, 127) 106 (100, 106) (95% CI) Min, Max7 

 .127 58.106 Kaplan-Meier estimates 

 (95% CI) 4 weeks from last 0.03 (0.08, 0.08) 0.00 (0.00, 0.00) dose^(d)8 weeks from last 0.24 (0.13, 0.34) 0.00 (0.00, 0.00) dose^(d) 12 weeksfrom last 0.45 (0.33, 0.58) 0.06 (0.00, 0.13) dose^(d) Percent recovery(95% CI) 

4 weeks from last 3.1 (0.4, 10.7) NE dose^(d) 8 weeks from last 23.1(13.5, 35.2) NE dose^(d) 12 weeks from last 43.1 (30.8, 56.0) 5.3 (0.6,17.7) dose^(d) (a) Time to testosterone recovery was defined as the timefrom 1 day after the last dose of Compound 1 or 4 weeks plus 1 day afterthe last dose of degarelix to testosterone recovery. Testosteronerecovery was defined as back to Baseline or >280 ng/dL, whichever occursfirst. It was censored for patients starting alternative ADT withoutrecovery at the last testosterone lab assessment before the start ofADT. ^(b)Baseline was defined as the value collected at the time closestto, but prior to, the start of study drug administration. The value<0.10 nmol/L (LLQ) was imputed as 0.10 nmol/L. (c) Probability of event(n = number of patients at risk). ^(d)4, 8 or 12 weeks from 1 day afterthe last dose of Compound 1 or 4, 8 or 12 weeks plus 1 day after thelast dose of degarelix.

indicates data missing or illegible when filed

A summary of time to serum testosterone recovery based on Kaplan-Meierestimates for the overall safety population is provided in FIG. 51. Themedian (95% CI) number of days to recovery was 91 (62, 127) days for theCompound 1 group and 100 (100, 106) days for the degarelix group.Patients treated with Compound 1 had a higher probability of achievingserum testosterone recovery throughout the study compared with patientstreated with degarelix as shown in FIG. 51. For patients who received atleast 12 weeks of treatment, the results were the same as the resultsfor the overall safety population. For patients who received treatmentfor at least 24 weeks, results were relatively similar to overallresults for both groups; however, for the Compound 1 group, the median(95% CI) number of days to recovery was 86 (58, 93) days and the percentrecovery (95% CI) by 12 weeks from the last dose was 46.0% (31.8%,60.7%). When serum testosterone recovery was estimated separately byreturn to baseline or greater than 280 ng/dL, there was a higherprobability for achievement of >280 ng/dL compared with achievement ofbaseline serum testosterone levels for the Compound 1 group.

Following discontinuation of therapy at the end of 24 weeks, patientswere followed for an additional 12 weeks to evaluate serum testosteronerecovery and associated changes in PSA and quality of life. At the endof the follow-up period approximately half of the patients receivingCompound 1 had recovered either to baseline testosterone values or togreater than 280 ng/dL, whichever was less, compared to only 6% ofpatients receiving degarelix. In the degarelix group there wasrelatively little LH recovery and median serum testosterone remained <50ng/dL at the end of study visit; serum testosterone met the definitionof recovery in only 6 of 38 patients. Patient-reported outcomes weresimilar in both treatment arms during the first 12 weeks of treatment,consistent with acute medical castration. There was a trend towards morerapid relief from hormonal and sexual related symptoms in the Compound1-treated group (e.g., hot flashes).

The median testosterone at the week 28/EOT visit was 93.9 ng/dL (Table10). This was 4 weeks after stopping Compound 1. Thus, mediantestosterone at 4 weeks after stopping treatment was well above the 50ng/dL castration threshold. In comparison, the median testosterone was9.6 ng/dL for degarelix at the same time point (week 28/EOT), 16.1 ng/dLat 8 weeks out (Week 32/follow-up), and 30.0 ng/dL at 12 weeks out (Week36/EOS). Thus, with injectable GnRH antagonist (degarelix), testosteronewas still suppressed under the castration threshold 12 weeks after 24week study (16 weeks after that last monthly injection of degarelix).

TABLE 10 Recovery of LII and Testosterone over Time from Associated PSALevels Compound 1 120 mg QD Degarefix 80 mg Q4W (N = 65) (N = 38) MedianLH, Median Median PSA, Median LH, Median Median PSA, mIU/mL testoserone,μg/L mlU/mL testosterone, μg/L (range) ng/dL (range) (range) (range)ng/dL (range) (range) Baseline 4.7 355.7 7.3 4.8 403.8  7.3  (0.8-32.2)(148.9-1289.1)   (2.6-31.6)  (1.3-42.0) (136.0-937.4)   (2.5-88.9) Week24 0.1  8.1  0.07 0.1  6.9 0.1  (0.1-3.9)  (3.2-125.0) (0.07-1.6)(0.1-3.7) (2.9-272.7) (0.07-1.9) Week 28/ 3.1  93.9  0.07 0.2  9.6 0.07EOT visit (0.2-15.7) (2.9-818.5) (0.07-1.5) (0.1-2.8) (2.9-224.9)(0.07-2.1) Week 32/ 8.3 238.3 0.2 0.5 16.1 0.07 follow-up (0.1-32.4)(10.1-928.5)  (0.07-3.2) (0.1-7.7) (3.2-262.9) (0.07-2.2) Week 36/ 10.7 256.9 0.2 1.4 30.0 0.07 EOS (0.1-38.7) (9.5-858.5) (0.07-2.3) (0.1-15.7) (3.7-378.7) (0.07-2.0) EOS = end of study EOT = end oftreatment. LH = luteinizing hormone PSA = prostate-specific antigen Q4W= once every 4 weeks QD = once daily

From EOT through the EOS, QoL such as AMS and sexual activity scoresappeared to improve more in the Compound 1 than the degarelix group,consistent with the observed pattern of testosterone recovery (Table11). Following discontinuation of study drug treatment at the end ofWeek 24 (or 4 weeks after the final injection of degarelix at Week 21,Day 1), the recovery of testosterone and associated changes in PSA werefollowed for an additional 12 weeks. Nearly half of patients receivingCompound 1 had recovered by 8 weeks of follow-up to either baselinevalues or >280 ng/dL, with little apparent recovery over the subsequent4 weeks (12 weeks follow-up). In contrast, only 6% of patients receivingdegarelix had recovered by the 12-week Follow-up time point. There wereminimal differences in change of PSA during the recovery period, about a0.2 to 0.4 ng/mL increase in patients receiving Compound 1. Based onrelative stability between the 8 and 12-week Follow-up time point, thisrecovery may have been related to PSA secretion from residual normalprostate rather than neoplastic tissue. The results suggest that therapid recovery of testosterone in the Compound 1 group following 24weeks neoadjuvant adjuvant to EBRT treatment for intermediate riskprostate cancer poses no significant risk regarding long term treatmentoutcomes.

TABLE 11 Change in QoL During Treatment (from Baseline to Week 25) orRecovery (from Week 25 to Week 36) Hormonal treatment- Globalhealth/QoL* Sexual activity related symptoms^(†) Compound 1 DegarelixCompound 1 Degarelix Compound 1 Degarelix 120 mg QD 80 mg Q4W 120 mg QD80 mg Q4W 120 mg QD 80 mg Q4W (N = 65) (N = 38) (N = 65) (N = 38) (N =65) (N = 38) Change from baseline (day 1) to week 25 n 60 38 60 38 60 38Mean (SD) −10.1 (18.9)  −7.5 (13.7) −19.7 (29.4)  −11.8 (36.3)  13.4(12.1) 12.9 (10.4) Change from week 25 to week 36 n 58 38 58 38 68 38Mean (SD)   2.3 (16.6)   0.7 (15.5) 12.1 (21.8)   6.6 (22.8) −6.0 (10.3)−1.2 (9.1)  Change from baseline to week 36 (EOS) n 62 38 62 38 62 38Mean (SD) −7.7 (17.8) −6.8 (16.0) −7.3 (30.0) −5.3 (34.7)  8.6 (11.3)11.7 (10.2) EOS = end of study, Q4W = once every 4 weeks, QD = oncedaily, QoL = quality of life, SD = standard deviation. *Higher scores ofglobal health/QoL and sexual activity reflect better QoL ^(†)Higherscores of hormonal treatment-related symptoms reflect worse QoL.

In summary, this study demonstrated rapid and sustained suppression ofserum testosterone levels for the 24 week treatment duration.Importantly, in this study, the serum testosterone recovery followingthe last dose of treatment was more rapid in the Compound 1 arm than inthe degarelix arm.

Example 10: Phase 1, Open-Label, Randomized, Three-Way Crossover StudyEvaluating the Relative Bioavailability and Effect of Food on Compound 1Tablet Formulations in Healthy Subjects

This was an open-label, randomized, 3-way crossover, single-dose studydesigned to evaluate the oral bioavailability of two Compound 1 tabletformulation candidates (T4 Formulation B and T4 Formulation C) relativeto a third Compound 1 tablet formulation (T2 Formulation), and theeffect of food on the PK of Compound 1 following oral administration ofthe T4 Formulations B and C. There were five single-dose treatmentregimens:

-   -   Regimen A: Compound 1, 120 mg dose T2 Formulation under fasted        conditions.    -   Regimen B: Compound 1, 120 mg T4 Formulation B under fasted        conditions.    -   Regimen C: Compound 1, 120 mg T4 Formulation B under fed        conditions (standard US Food and Drug Administration [FDA]        high-fat, high-calorie breakfast).    -   Regimen D: Compound 1, 120 mg T4 Formulation C under fasted        conditions.    -   Regimen E: Compound 1, 120 mg T4 Formulation C under fed        conditions (standard US FDA high-fat, high-calorie breakfast).

Screening assessments were performed within 28 days before the Day 1dose of Compound 1. Following confirmation of eligibility, subjects wererandomly assigned to a sequence in one of two treatment arms:

-   -   Arm 1: T2 Formulation (Regimen A to serve as a reference group)        and T4 Formulation B (Regimens B and C).    -   Arm 2: T2 Formulation (Regimen A to serve as a reference group)        and T4 Formulation C (Regimens D and E).

In each study arm, each subject participated in 3 treatment periods witha 10-day washout interval between each dose. Subjects received a single120 mg oral dose of Compound 1 on Day 1, Day 11, and Day 21, per theassigned arm and sequence, followed by serial blood sampling for PKassessments at predetermined time points up to 120 hours postdose.During each of the 3 treatment periods, subjects were confined to theclinical site for a total of 4 days. Each eligible subject was to checkinto the clinical site on the evening of Day −1 and undergo baselinesafety assessments.

Subjects were confined to the clinical site from Day −1 through Day 4.Following the Day 4 (72 hours postdose) PK blood sampling, subjects weredischarged from the clinical site. Subjects were instructed to return tothe study clinic on the morning of Day 5 for the 96-hour PK assessmentand on the morning of Day 6 for the 120-hour PK assessment. Subjectswere to return to the study clinic on the evening of Day 10 and wereconfined from Day 10 through Day 14. Following the Day 14 (72 hourspostdose) PK blood sampling, subjects were discharged from the clinicalsite. Subjects were instructed to return to the study clinic on themorning of Day 15 for the 96-hour PK assessment and the morning of Day16 for the 120-hour PK assessment. Subjects were to return to the studyclinic on the evening of Day 20 and were confined from Day 20 throughDay 24. Following the Day 24 (72 hours postdose) PK blood sampling,subjects were discharged from the clinical site. Subjects wereinstructed to return to the study clinic on the morning of Day 25 forthe 96-hour PK assessment on the morning of Day 26 for the 120-hour PKassessment. Study drug was administered in the morning of Days 1, 11,and 21 in either the fed or fasted state. During confinement, subjectsreceived standardized meals scheduled at the same time each day. Foreach subject, vital signs, physical examinations, adverse event (AE)assessments, laboratory values (chemistry, hematology, and urinalysis),and 12-lead electrocardiograms (ECGs) were obtained to evaluate thesafety and tolerability of Compound 1. Subjects were considered to havecompleted the study if they completed each of the 3 treatment periodsand the End-of-Study (EOS) assessment (30 days after the last dose ofstudy drug). Subjects could discontinue participation in the study atany time. Each subject must have been a healthy adult male, aged 18-55years (inclusive) to be included in this study. Tables 12 and 13summarize treatment Arm 1 and treatment Arm 2 of the study.

TABLE 12 Treatment Period Sequences for Arm 1 Sequence Period^(a) 1Period^(a) 2 Period^(a) 3 1 Regimen A^(b) Regimen B^(c) Regimen C^(d) 2Regimen A Regimen C Regimen B 3 Regimen B Regimen A Regimen C 4 RegimenB Regimen C Regimen A 5 Regimen C Regimen A Regimen B 6 Regimen CRegimen B Regimen A ^(a)The length of each treatment period was 10 days.Subjects received single doses of Compound 1 on the first day of eachtreatment period (i.e., Day 1, Day 11, and Day 21). ^(b)Regimen A:Compound 1, 120 mg dose (80 mg + 40 mg tablets) T2 Formulation underfasted conditions. ^(c)Regimen B: Compound 1, 120 mg (1 × 120 mg tablet)T4 Formulation B under fasted conditions. ^(d)Regimen C: Compound 1, 120mg (1 × 120 mg tablet) T4 Formulation B under fed conditions (standardUS FDA high-fat, high-calorie breakfast).

TABLE 13 Treatment period sequences for Arm 2 Sequence Period^(a) 1Period³ 2 Period³ 3 1 Resimen A^(b) Regimen D^(c) Regimen E^(d) 2Regimen A Regimen E Regimen D 3 Regimen D Regimen A Regimen E 4 RegimenD Regimen E Regimen A 5 Regimen E Regimen A Regimen D 6 Regimen ERegimen D Regimen A ^(a)The length of each treatment period was 10 days.Subjects received single doses of Compound 1 on the first day of eachtreatment period (i.e., Day 1, Day 11, and Day 21). ^(b)Regimen A:Compound 1, 120 mg dose (80 mg + 40 mg tablets) T2 Formulation underfasted conditions. ^(c)Regimen D: Compound 1, 120 mg (1 × 120 mg tablet)T4 Formulation C under fasted conditions. ^(d)Regimen E: Compound 1, 120mg (1 × 120 mg tablet) T4 Formulation C under fed conditions (standardUS FDA high-fat, high-calorie breakfast).

A total of 54 subjects enrolled in and completed the study. There were27 subjects in each arm of the study. All 54 subjects were included inthe safety population and the PK-evaluable population. No major protocoldeviations occurred for any subject during this study. One subject had aminor protocol deviation related to a dose administration interval thatoccurred greater than 30 minutes after the start of breakfast. In Period3, the subject was administered the T4 Formulation B under fedconditions; the starting time of Compound 1 dose administrationfollowing the start of breakfast was 31 minutes and 3 seconds. All ofthe PK parameters for this subject following oral administration of T4Formulation B under fed conditions were generally similar to the meanvalues of PK parameters in this treatment group; therefore, the PKparameters of this subject were included in the descriptive and ANOVAstatistical analyses. Tables 14 and 15 below provide summaries of somepharmacokinetic parameters following administration of the differentformulations.

TABLE 14 Summary Statistics of Plasma Pharmacokinetic Parameters ofCompound 1 Following Single Oral Administration of 120 mg Compound 1 asT4 Formulation B or C Tablet Compared to T2 Formulation Tablets UnderFasted Conditions Parameter (unit) Arm 1 Arm 2 Statistic T2 Form. T4Form. B T2 Form. T4 Form. C N 27 26 27 27 t_(max) (h) Median 2.01 3.003.00 3.00 Min, Max 0.500, 6.00 0.502, 12.0 0.499, 6.02 0.499, 12.0C_(max) (ng/mL) GM 46.7 42.0 52.0 43.5 CV % 115 153 93.3 147 AUC₁₂₀ (ng· h/mL) GM 447 440 532 415 CV % 64.7 83.3 55.4 85.1 AUC∞ (ng · h/mL) GM476 467 563 440 CV % 63.5 82.8 55.1 84.8 t_(1/2z) (h) Mean 36.3 36.1^(a)34.9 35.5 SD 4.40 4.90 4.13 4.22 Min, Max  28.8, 46.5  27.4, 44.7  29.2,44.8  25.4, 46.0 CV = geometric coefficient of variation; GM = geometricmean. ^(a)N = 27.

TABLE 15 Summary Statistics of Plasma Pharmacokinetic Parameters ofCompound 1 Following Single Oral Administration of 120 mg Compound 1 asT4 Formulation B or C Tablet Under Fed Conditions Parameter (unit) T4 T4Statistic Formulation B Formulation C N 27 27 t_(max) (h) Median 3.003.00 Min, Max 0.500, 8.00 1.00, 8.00 C_(max) (ng/mL) GM 33.0 41.2 CV %116 106 AUC₁₂₀ (ng · h/mL) GM 350 386 CV % 65.0 52.4 AUC∞ (ng · h/mL) GM372 409 CV % 64.1 51.8 t_(1/2z) (h) Mean 35.1 35.4 SD 4.11 2.97 Min, Max 29.9, 45.7 29.9, 42.2 CV = geometric coefficient of variation; GM =geometric mean.

All subjects included in this study were healthy men, a majority of whowere white (81%) and Hispanic or Latino (65%). The overall mean (SD) ageof study subjects was 38.9 (10.8) years, with an age range from 19 to 55years. The overall mean (SD) weight and BMI of subjects was 83.4 (12.7)kg and 27.2 (3.2) kg/m², respectively. Demographic characteristics weresimilar between treatment arms. No subjects were excluded from thePK-evaluable population; therefore, the demographics for this populationwere the same as the safety population. The formulation information forvarious formulations used in this example, and other exemplaryformulations, is provided in Table 16.

TABLE 16 Exemplary Formulations 1-20 mg 40 mg 40 mg 40 mg 120 mg 120 mgFunction (T1) (T2) (T3) (T4-B) (T4-B) (T4-C) Compound 1 DS  1-20 40 4040 120 120 Mannitol Diluent 80-61 122 122 51 153 234 MicrocrystallineDiluent 10 20 40 — — 30 cellulose Polyethylene Lubricant — — — — — 1.8Glycol 8000 Hydroxypropyl Binder 3 6 6 3 9 11.4 cellulose CroscarmelloseDisintegrant 5 10 10 — — 19.05 sodium Sodium starch Disintegrant — — — 515 — glycolate Magnesium Lubricant 1 2 2 1 3 3.75 stearate Purifiedwater* solvent q.s q.s q.s q.s q.s q.s Sub total (Core 100 220 220 100300 420 tablets) Hypromellose Film 2.93 7.12 7.12 3.56 10.68 13.5 2910coating Polyethylene plasticizer 0.67 — — — — — glycol 8000 TitaniumPigment 0.33 0.8 0.8 0.4 1.2 1.5 dioxide Ferric oxide, red Colorant 0.070.02 0.02 0.04 0.12 0.15 Ferric oxide, Colorant — — 0.06 — — — yellowPurified water* q.s q.s q.s q.s q.s q.s Sub total (FC 4 8 8 4 12 15.15layer) Total 104 228 228 104 312 435.15 Carnauba Wax — — 0.012 0.0040.008 q.s

Example 11: A Study to Evaluate the Safety and Efficacy of Compound 1 inPatients with Androgen-Sensitive Advanced Prostate Cancer

This study is a phase 3 multinational randomized, open-label,parallel-group study to evaluate the safety and efficacy of Compound 1,or a pharmaceutically acceptable salt thereof, in patients withandrogen-sensitive advanced prostate cancer who require at least 1 yearof continuous androgen deprivation therapy (FIG. 54). Compound 1 is anoral gonadotropin-releasing hormone (GnRH) receptor antagonist thatlowers testosterone by inhibiting pituitary release offollicle-stimulating hormone (FSH) and luteinizing hormone (LH).Compound 1 120 mg orally once daily or leuprolide acetate depotsuspension, 22.5 mg (or 11.25 mg in some Asian countries), every3-months (3-M) will be administered to patients with prostate cancer whorequire androgen deprivation therapy. This study will evaluate theability of Compound 1, or a pharmaceutically acceptable salt thereof, toachieve and maintain serum testosterone suppression to castrate levels(≤50 ng/dL [1.7 nmol/L]) for 48 weeks in patients withandrogen-sensitive advanced prostate cancer.

To be eligible for the study, a patient must be, in the opinion of theinvestigator, a candidate for at least 1 year of continuous androgendeprivation therapy for the management of androgen-sensitive advancedprostate cancer and must not be a candidate for surgical therapy.Eligible patients include those with evidence of biochemical relapse(rising PSA) following local primary intervention with curative intent,newly diagnosed metastatic disease (excluding metastases to the brain),and/or advanced localized disease. Patients may receive radiotherapy,cryotherapy or high frequency ultrasound no sooner than 2 months afterinitiation of androgen deprivation therapy. Patients may be included ifthey have not previously received androgen deprivation therapy for morethan 12 months, and if the androgen deprivation therapy was completed atleast 12 months prior to baseline. Patients previously treated withtaxanes or expected to receive taxanes after initiation of androgendeprivation therapy are excluded, as are patients receiving androgendeprivation therapy adjuvant or neoadjuvant to radiotherapy as primarydefinitive therapy. Baseline serum testosterone must be ≥150 ng/dL (5.2nmol/L) to be enrolled.

Patients enrolled in this study will be randomized 2:1 to receive oralCompound 1 120 mg once daily following a loading dose of 360 mg on Day 1or leuprolide acetate 3-M depot 22.5 mg (or 11.25 mg in some Asiancountries), plus an antiandrogen for the first 4 weeks or longer ifindicated in the opinion of the investigator. Randomization will bestratified by geographic region, presence of metastatic disease, andage.

Approximately 1125 patients will be enrolled in this study fromapproximately 200 study centers in North and South America, Europe, andthe Asia-Pacific region. The study includes a Screening Period of up to28 days, a Treatment Period of 48 weeks, and a Follow-up Period of up to90 days (with visits at 30 and 60 days after the treatment period ends).Additionally, unscheduled follow-up visit(s) may be arranged forpatients with study-related safety concerns as needed. Eligible patientswill receive study treatment for 48 weeks. During that time,testosterone and PSA will be assessed monthly and patient-reportedoutcomes (European Organisation of Research and Treatment of Cancer[EORTC] QLQ-C30, European Quality of Life 5-Dimension 5-Levelquestionnaire [EuroQol EQ-5D-5L]) will be assessed approximately every 3months during the Treatment Period and more frequently during theFollow-up Period. Additional serum endocrine evaluations will include:LH, FSH, dihydrotestosterone, and sex hormone binding globulin. Compound1 pharmacokinetic (PK) samples will be collected throughout the study.Full PK profiles will be determined in a subset of patients in Asia.Time to testosterone recovery will be measured in approximately 100patients randomized to Compound 1 and approximately 50 patientsrandomized to leuprolide acetate who complete 48 weeks of treatment andwho do not plan to start alternative androgen deprivation therapy withinthe following 12 weeks (or within 24 weeks following the last injectionof leuprolide acetate 3-M depot). Safety assessments will includetreatment-emergent adverse events, vital signs, physical examinations,clinical laboratory tests, 12-lead electrocardiograms (ECG), and visualacuity tests.

Patients with disease progression during the treatment period, in thesetting of testosterone suppression to castrate levels (testosteronelevel ≤50 ng/dL [1.7 nmol/L]), should remain on study and may receiveadditional oral therapy, systemic antineoplastic, and/or radiotherapy asprescribed by the investigator.

The primary endpoint of the study is sustained castration rate definedas the cumulative probability of testosterone suppression to ≤50 ng/dL(1.7 nmol/L) while on study treatment from Week 5 Day 1 (Study Day 29)through Week 49 Day 1 (Study Day 337).

Secondary Endpoints Include:

Castration rate defined as the cumulative probability of testosteronesuppression to ≤50 ng/dL (1.7 nmol/L) prior to dosing on Week 1 Day 4,prior to dosing on Week 2, and prior to dosing on Week 3;

Profound castration rate defined as the cumulative probability oftestosterone suppression to ≤20 ng/dL (0.7 nmol/L) while on studytreatment from Week 25 Day 1 through Week 49 Day 1;

Time to testosterone recovery in the first 100 patients randomized toCompound 1, or a pharmaceutically acceptable salt thereof, and the first50 patients randomized to leuprolide acetate who complete 48 weeks oftreatment and who do not plan to start alternative androgen deprivationtherapy within the following 12 weeks (or within 24 weeks following thelast injection of leuprolide acetate 3-M depot);

Proportion of patients with confirmed PSA response by Prostate CancerClinical Trials Working Group 3 guidelines at the Week 2 and 5 visits;

Proportion of patients with PSA concentration <0.2 ng/mL (0.2 μg/L) atthe Week 25 visit;

Absolute values and changes from baseline in the scores of theEORTC-QLQ-C30 global health domain, and the EORTC-QLQ-PR25 sexualactivity and hormonal-treatment-related symptom subdomains, at regularintervals during treatment, and as applicable during the Follow-upand/or at End of Treatment visits;

Absolute values and changes from baseline of the remaining domains inthe EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the EuroQol EQ-5D-5Lquestionnaire, at regular intervals during treatment, and as applicableduring the Follow-up visits;

Incidence of adverse events;

Incidence of abnormalities in clinical laboratory data;

Endocrine marker effects of Compound 1 and leuprolide acetate asmeasured as absolute value and change from baseline for: LH at the Week2, Week 3, and Week 5 visits, and then every 4 weeks until the lastfollow-up visit; FSH at the Week 5, Week 13, Week 25, Week 37, and Week49 visits; Dihydrotestosterone at the Week 5, Week 13, Week 25, Week 37,and Week 49 visits; and Sex hormone binding globulin at the Week 13,Week 25, and Week 49 visits;

Predose Compound 1 plasma concentrations;

Single and repeat-dose plasma Compound 1 PK parameters such as maximumplasma concentration (C_(max)), area under the concentration-time curvefrom time 0 to the end of the dosing interval (AUC_(0-τ)), and time tomaximum plasma concentration (t_(max)) in a subset of patients from Asiaduring the Day 1 visit.

Exploratory Endpoints Include:

Overall survival defined as time from randomization to date of deathprior to data cutoff date; and

The presence of polymorphisms in germline genes related to thehypothalamic-pituitary-androgen pathway, prostate cancer risk, or todrug metabolizing enzymes and transporter proteins that might beimplicated in the drug disposition, safety, or efficacy of Compound 1.

EXEMPLARY EMBODIMENTS

Some embodiments of this disclosure relate to Embodiment I, as follows:

Embodiment I-1

A method for treating prostate cancer in a subject in need of anincrease in serum testosterone levels to a level above 50 ng/dL, themethod comprising administering to the subject once-daily an oralformulation comprising about 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,wherein when the once-daily administration is suspended for a suspensionperiod, the subject experiences an increase of serum testosteronelevels.

Embodiment I-2

A method for treating prostate cancer in a subject in need thereof, themethod comprising:

administering to the subject once-daily an oral formulation comprisingabout 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;

suspending administration of the oral formulation for a suspensionperiod to allow for an increase of serum testosterone levels; and

resuming administering to the subject once-daily the oral formulation atthe end of the suspension period.

Embodiment I-3

The method of embodiment I-1, wherein after the suspension period,administration is not resumed.

Embodiment I-4

The method of embodiment I-2, wherein the serum testosterone levelincreases to above medical castration level.

Embodiment I-5

The method of any one of the preceding embodiments, wherein the serumtestosterone level increases to greater than about 55 ng/dL.

Embodiment I-6

The method of any one of the preceding embodiments, wherein the serumtestosterone level increases to greater than about 350 ng/dL.

Embodiment I-7

The method of any one of embodiments I-1 through I-3, wherein the serumtestosterone level increases to about 300 ng/dL to about 600 ng/dL.

Embodiment I-8

The method of any one of the preceding embodiments, wherein the serumtestosterone level increases to the subject's serum testosterone levelprior to administration of the oral formulation.

Embodiment I-9

The method of embodiment I-8, wherein the serum testosterone levelincreases to the subject's serum testosterone level prior toadministration of the oral formulation within 7 days of the beginning ofthe suspension period.

Embodiment I-10

The method of embodiment I-8, wherein the serum testosterone levelincreases to the subject's serum testosterone level prior toadministration of the oral formulation within 45 days of the beginningof the suspension period.

Embodiment I-11

The method of any one of the preceding embodiments, wherein the serumtestosterone level increase occurs within 7 days of the beginning of thesuspension period.

Embodiment I-12

The method of any one of the preceding embodiments, wherein the prostatecancer is hormone dependent prostate cancer.

Embodiment I-13

The method of any one of the preceding embodiments, wherein the prostatecancer is advanced prostate cancer.

Embodiment I-14

The method of any one of the preceding embodiments, wherein the prostatecancer is metastatic, non-metastatic, locally advanced, advanced hormonesensitive, advanced castration resistant, or recurrent.

Embodiment I-15

The method of any one of the preceding embodiments, wherein saidadministering comprises administration once-daily of an oral load doseformulation of from about 240 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for 1-3 days at the beginning of treatment.

Embodiment I-16

The method of any one of the preceding embodiments, wherein saidadministering comprises administration once-daily of an oral load doseformulation of from about 240 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for 1-3 days at the beginning of treatment after the suspension period.

Embodiment I-17

The method of any one of the preceding embodiments, wherein saidadministering comprises administration once-daily of an oral maintenancedose formulation of from about 80 mg to about 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-18

The method of embodiment I-17, wherein the oral maintenance doseformulation administration begins on the day after administering thelast dose of the oral load dose formulation.

Embodiment I-19

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 52 weeks.

Embodiment I-20

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 36 weeks.

Embodiment I-21

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 24 weeks.

Embodiment I-22

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 12 weeks.

Embodiment I-23

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 8 weeks.

Embodiment I-24

The method of any one of embodiments I-1 through I-18, wherein saidsuspension period is up to 4 weeks.

Embodiment I-25

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's prostate-specificantigen (PSA) level is ≥20% of the subject's PSA level of the nadirduring treatment.

Embodiment I-26

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level is ≥50%of the subject's PSA level prior to treatment.

Embodiment I-27

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level isgreater than the subject's PSA level at the beginning of the suspensionperiod.

Embodiment I-28

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject experiences return ofsymptoms of prostate cancer.

Embodiment I-29

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level is ≥3ng/mL.

Embodiment I-30

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level is ≥10ng/mL.

Embodiment I-31

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level is ≥20ng/mL.

Embodiment I-32

The method of any one of the preceding embodiments, wherein thesuspension period is discontinued when the subject's PSA level is ≥30ng/mL.

Embodiment I-33

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 12 consecutive weeks or greater.

Embodiment I-34

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 24 consecutive weeks or greater.

Embodiment I-35

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 48 consecutive weeks or greater.

Embodiment I-36

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 52 consecutive weeks or greater.

Embodiment I-37

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 72 consecutive weeks or greater.

Embodiment I-38

The method of any one of the preceding embodiments, wherein the oralformulation is administered for 96 consecutive weeks or greater.

Embodiment I-39

The method of any one of embodiments I-1 through I-32, whereinadministration is suspended after at least 24 consecutive weeks oftreatment.

Embodiment I-40

The method of embodiment I-39, wherein administration is suspended afterat least 36 consecutive weeks of treatment.

Embodiment I-41

The method of embodiment I-39, wherein administration is suspended afterat least 52 consecutive weeks of treatment.

Embodiment I-42

The method of any one of the preceding embodiments, wherein the subjectis in need of an increase in serum testosterone levels due to anintercurrent illness, receiving radiation therapy, while bedridden,having suffered an injury, having a surgical procedure or other invasiveprocedure, or a desire for a period of restored sexual function.

Embodiment I-43

The method of any one of embodiments I-1 through I-41, wherein thesubject is in need of an increase in serum testosterone levels due to anintercurrent illness or surgical or other invasive procedure withprojected full recovery time of at least two weeks.

Embodiment I-44

The method of embodiment I-42 or 1-43, wherein administration issuspended prior to the surgical or other invasive procedure or radiationtherapy.

Embodiment I-45

The method of embodiment I-42 or 1-43, wherein administration issuspended after the surgical or other invasive procedure, injury, orradiation therapy.

Embodiment I-46

The method of any one of embodiments I-42 through I-45, whereinadministration is suspended during the surgical or other invasiveprocedure, injury, or radiation therapy.

Embodiment I-47

The method of embodiment I-42 or I-43, wherein administration occursprior to and during the surgical or other invasive procedure orradiation therapy and administration is suspended after the surgery orother invasive procedure or radiation therapy.

Embodiment I-48

The method of any one of embodiments I-42 through I-47, wherein thesurgical procedure is heart surgery, knee replacement, hip replacement,abdominal surgery, pelvic surgery, vascular surgery, spine surgery, oran emergency procedure due to injury.

Embodiment I-49

The method of any one of embodiments I-42 through I-48, wherein thesubject is identified as at risk for acute postoperative frailty.

Embodiment I-50

The method of embodiment I-42 or I-43, wherein administration issuspended during the intercurrent illness or while the subject isbedridden.

Embodiment I-51

The method of any one of embodiments I-43 through I-49, whereinadministration resumes after the subject is recovered from theintercurrent illness, is no longer bedridden, has resumed normalactivities of daily living, or has regained a normal level of function.

Embodiment I-52

The method of any one of the preceding embodiments, wherein the serumtestosterone level is above medical castration levels within 7 days ofthe suspension of administration.

Embodiment I-53

The method of any one of embodiments I-15 through I-52, wherein the oralload dose formulation comprises about 240 mg, about 360 mg, or about 480mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-54

The method of embodiment I-53, wherein the oral load dose formulationcomprises about 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-55

The method of any one of embodiments I-17 through I-54, wherein the oralmaintenance dose formulation comprises about 80 mg, about 120 mg, orabout 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-56

The method of embodiment I-55, wherein the oral maintenance doseformulation comprises about 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-57

The method any one of embodiments I-17 through I-54, wherein the oralload dose formulation comprises about 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and is administered once on day 1 of treatment, and the oral maintenanceformulation comprises about 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and is administered once-daily.

Embodiment I-58

The method of any one of embodiments I-1 through I-14 or I-19 throughI-52, wherein the oral formulation comprises about 80 mg to about 160 mgofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-59

The method of any one of the preceding embodiments, wherein theadministering is pre-prandial.

Embodiment I-60

The method of any one of the preceding embodiments, wherein theadministering is at least 1 hour before eating or at least 2 hours aftereating.

Embodiment I-61

The method of any one of embodiments I-1 through I-58, wherein theadministering is at least 30 minutes before eating or while subject isfasting.

Embodiment I-62

The method of any one of the preceding embodiments, wherein the oralformulation, oral load dose formulation and oral maintenance doseformulation are immediate release formulations.

Embodiment I-63

The method of any one of embodiments I-17 through I-52, wherein the oralmaintenance dose formulation comprises 102 mg to 204 mg of mannitol, 6mg to 12 mg of hydroxypropyl cellulose, 10 mg to 20 mg of sodium starchglycolate, and 2 mg to 4 mg of magnesium stearate.

Embodiment I-64

The method of any one of the preceding embodiments, further comprisingadministering an anti-androgen.

Embodiment I-65

The method of embodiment I-64, wherein the anti-androgen is selectedfrom the group consisting of flutamide, nilutamide, bicalutamide,enzalutamide, apalutamide, cyproterone acetate, megestrol acetate,chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide (fluridil), and cimetidine.

Embodiment I-66

The method of any one of the preceding embodiments, further comprisingadministering a CYP17 lyase inhibitor.

Embodiment I-67

The method of embodiment I-66, wherein the CYP17 lyase inhibitor isabiraterone.

Embodiment I-68

The method of any one of the preceding embodiments, wherein thesubject's serum testosterone level is suppressed prior to and after thesuspension of administration.

Embodiment I-69

The method of any one of embodiments I-1 through I-63 or I-66 throughI-68, wherein the method does not comprise administration of ananti-androgen.

Embodiment I-70

The method of any one of the preceding embodiments, wherein the methoddoes not comprise administration of prednisone.

Embodiment I-71

The method of any one of embodiments I-1 through I-69, wherein themethod further comprises administration of prednisone.

Embodiment I-72

The method of any one of the preceding embodiments, further comprisingthe step of suspending administration for a subsequent suspension periodafter completion of the suspension period and resumption ofadministration.

Embodiment I-73

The method of embodiment I-72, wherein the subsequent suspension periodoccurs at least 12 weeks after resuming once-daily administration of theoral formulation comprising about 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-74

The method any one of the preceding embodiments, wherein the prostatecancer is castration-resistant metastatic prostate cancer.

Embodiment I-75

The method any one of the preceding embodiments, wherein the prostatecancer is castration-resistant non-metastatic prostate cancer.

Embodiment I-76

The method any one of the preceding embodiments, wherein the prostatecancer is hormone-sensitive metastatic prostate cancer.

Embodiment I-77

The method any one of the preceding embodiments, wherein the prostatecancer is hormone-sensitive non-metastatic prostate cancer.

Embodiment I-78

The method of any one of the preceding embodiments, wherein within about4 to about 8 days of first administering the oral formulation, or oralload dose formulation and oral maintenance dose formulation, the serumtestosterone levels in the subject are at or below medical castrationlevel.

Embodiment I-79

The method of embodiment I-78, wherein within 4 days of firstadministering the oral formulation, or oral load dose formulation andoral maintenance dose formulation, the serum testosterone levels in thesubject are at or below medical castration level.

Embodiment I-80

An oral formulation comprising about 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for use in a method of treating prostate cancer in a subject in needthereof.

Embodiment I-81

The formulation for use according to Embodiment I-80, wherein thesubject is in need of an increase in serum testosterone levels to alevel above 50 ng/dL.

Embodiment I-82

The formulation for use according to Embodiment I-80 or Embodiment I-81,wherein the method comprises administering the oral formulation to thesubject once daily.

Embodiment I-83

The formulation for use according to any one of Embodiment I-80 toEmbodiment I-82, wherein when the once daily administration is suspendedfor a suspension period, the subject experiences an increase of serumtestosterone levels.

Embodiment I-84

The formulation for use according to Embodiment I-83, wherein after thesuspension period, administration is not resumed.

Embodiment I-85

An oral formulation comprising about 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for use in a method for treating prostate cancer in a subject in needthereof, the method comprising:

administering the oral formulation to the subject once daily;

suspending administration of the oral formulation for a suspensionperiod to allow for an increase of serum testosterone levels; and

resuming administering to the subject once daily the oral formulation atthe end of the suspension period.

Embodiment I-86

The formulation for use according to Embodiment I-85, wherein theincrease in serum testosterone level is an increase to above medicalcastration level.

Embodiment I-87

The formulation for use according to any one of Embodiments I-80 toI-86, wherein the increase in serum testosterone level is an increase togreater than about 55 ng/dL.

Embodiment I-88

The formulation for use according to any one of Embodiments I-80 toI-87, wherein the increase in serum testosterone level is an increase togreater than about 350 ng/dL.

Embodiment I-89

The formulation for use according to any one of Embodiments I-80 toI-86, wherein the increase in serum testosterone level is an increase toabout 300 ng/dL to about 600 ng/dL.

Embodiment I-90

The formulation for use according to any one of Embodiments I-80 toI-89, wherein the prostate cancer is hormone dependent prostate cancer.

Embodiment I-91

The formulation for use according to any one of Embodiments I-80 toI-90, wherein the prostate cancer is advanced prostate cancer.

Embodiment I-92

The formulation for use according to any one of Embodiments I-80 toI-91, wherein the prostate cancer is metastatic, non-metastatic, locallyadvanced, advanced hormone sensitive, advanced castration resistant, orrecurrent.

Embodiment I-93

The formulation for use according to any one of Embodiments I-80 toI-92, wherein said administering comprises administration once daily ofan oral load dose formulation of from about 240 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for 1-3 days at the beginning of treatment.

Embodiment I-94

The formulation for use according to any one of Embodiments I-80 toI-93, wherein said administering comprises administration once daily ofan oral load dose formulation of from about 240 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,for 1-3 days at the beginning of treatment after the suspension period.

Embodiment I-95

The formulation for use according to any one of Embodiments I-80 toI-94, wherein said administering comprises administration once daily ofan oral maintenance dose formulation of from about 80 mg to about 160 mgofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-96

The formulation for use according to Embodiment I-95, wherein the oralmaintenance dose formulation administration begins on the day afteradministering the last dose of the oral load dose formulation.

Embodiment I-97

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 52 weeks.

Embodiment I-98

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 36 weeks.

Embodiment I-99

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 24 weeks.

Embodiment I-100

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 12 weeks.

Embodiment I-101

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 8 weeks.

Embodiment I-102

The formulation for use according to any one of Embodiments I-80 toI-96, wherein said suspension period is up to 4 weeks.

Embodiment I-103

The formulation for use according to any one of Embodiments I-80 toI-102, wherein the suspension period is discontinued when the subject'sprostate-specific antigen (PSA) level is ≥20% of the subject's PSA levelof the nadir during treatment.

Embodiment I-104

The formulation for use according to any one of Embodiments I-80 toI-103, wherein the suspension period is discontinued when the subject'sPSA level is ≥50% of the subject's PSA level prior to treatment.

Embodiment I-105

The formulation for use according to any one of Embodiments I-80 toI-104, wherein the suspension period is discontinued when the subject'sPSA level is greater than the subject's PSA level at the beginning ofthe suspension period.

Embodiment I-106

The formulation for use according to any one of Embodiments I-80 toI-105, wherein the suspension period is discontinued when the subjectexperiences return of symptoms of prostate cancer.

Embodiment I-107

The formulation for use according to any one of Embodiments I-80 toI-106, wherein the suspension period is discontinued when the subject'sPSA level is ≥3 ng/mL.

Embodiment I-108

The formulation for use according to any one of Embodiments I-80 toI-107, wherein the suspension period is discontinued when the subject'sPSA level is ≥10 ng/mL.

Embodiment I-109

The formulation for use according to any one of Embodiments I-80 toI-108, wherein the suspension period is discontinued when the subject'sPSA level is ≥20 ng/mL.

Embodiment I-110

The formulation for use according to any one of Embodiments I-80 toI-109, wherein the suspension period is discontinued when the subject'sPSA level is ≥30 ng/mL.

Embodiment I-111

The formulation for use according to any one of Embodiments I-80 toI-110, wherein the oral formulation is administered for 12 consecutiveweeks or greater.

Embodiment I-112

The formulation for use according to any one of Embodiments I-80 toI-111, wherein the oral formulation is administered for 24 consecutiveweeks or greater.

Embodiment I-113

The formulation for use according to any one of Embodiments I-80 toI-112, wherein the oral formulation is administered for 48 consecutiveweeks or greater.

Embodiment I-114

The formulation for use according to any one of Embodiments I-80 toI-113, wherein the oral formulation is administered for 52 consecutiveweeks or greater.

Embodiment I-115

The formulation for use according to any one of Embodiments I-80 toI-114, wherein the oral formulation is administered for 72 consecutiveweeks or greater.

Embodiment I-116

The formulation for use according to any one of Embodiments I-80 toI-115, wherein the oral formulation is administered for 96 consecutiveweeks or greater.

Embodiment I-117

The formulation for use according to any one of Embodiments I-80 toI-110, wherein administration is suspended after at least 24 consecutiveweeks of treatment.

Embodiment I-118

The formulation for use according to Embodiment I-117, whereinadministration is suspended after at least 36 consecutive weeks oftreatment.

Embodiment I-119

The formulation for use according to Embodiment I-117, whereinadministration is suspended after at least 52 consecutive weeks oftreatment.

Embodiment I-120

The formulation for use according to any one of Embodiments I-93 toI-119, wherein the oral load dose formulation comprises about 240 mg,about 360 mg, or about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-121

The formulation for use according to Embodiment I-120, wherein the oralload dose formulation comprises about 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-122

The formulation for use according to any one of Embodiments I-95 toI-121, wherein the oral maintenance dose formulation comprises about 80mg, about 120 mg, or about 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-123

The formulation for use according to Embodiment I-122, wherein the oralmaintenance dose formulation comprises about 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-124

The formulation for use according to any one of Embodiments I-95 toI-121, wherein the oral load dose formulation comprises about 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and is administered once on day 1 of treatment, and the oral maintenanceformulation comprises about 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and is administered once daily.

Embodiment I-125

The formulation for use according to any one of Embodiments I-80 to I-92or Embodiments I-97 to I-119, wherein the oral formulation comprisesabout 80 mg to about 160 mg of ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-126

The formulation for use according to any one of Embodiments I-80 toI-125, wherein the administering is pre-prandial.

Embodiment I-127

The formulation for use according to any one of Embodiments I-80 toI-126, wherein the administering is at least 1 hour before eating or atleast 2 hours after eating.

Embodiment I-128

The formulation for use according to any one of Embodiments I-80 toI-125, wherein the administering is at least 30 minutes before eating orwhile subject is fasting.

Embodiment I-129

The formulation for use according to any one of Embodiments I-80 toI-128, wherein the oral formulation, oral load dose formulation and oralmaintenance dose formulation are immediate release formulations.

Embodiment I-130

The formulation for use according to any one of Embodiments I-95 toI-119, wherein the oral maintenance dose formulation comprises 102 mg to204 mg of mannitol, 6 mg to 12 mg of hydroxypropyl cellulose, 10 mg to20 mg of sodium starch glycolate, and 2 mg to 4 mg of magnesiumstearate.

Embodiment I-131

The formulation for use according to any one of Embodiments I-80 toI-130, wherein the method further comprises administering ananti-androgen.

Embodiment I-132

The formulation for use according to Embodiment I-131, wherein theanti-androgen is selected from the group consisting of flutamide,nilutamide, bicalutamide, enzalutamide, apalutamide, cyproteroneacetate, megestrol acetate, chlormadinone acetate, spironolactone,canrenone, drospirenone, ketoconazole, topilutamide (fluridil), andcimetidine.

Embodiment I-133

The formulation for use according to any one of the Embodiments I-80 toI-132, wherein the method further comprises administering a CYP17 lyaseinhibitor.

Embodiment I-134

The formulation for use according to Embodiment I-133, wherein the CYP17lyase inhibitor is abiraterone.

Embodiment I-135

The formulation for use according to any one of Embodiments I-80 toI-130 or I-133 to I-134, wherein the method does not compriseadministration of an anti-androgen.

Embodiment I-136

The formulation for use according to any one of Embodiments I-80 toI-135, wherein the method does not comprise administration ofprednisone.

Embodiment I-137

The formulation for use according to any one of Embodiments I-80 toI-135, wherein the method further comprises administration ofprednisone.

Embodiment I-138

The formulation for use according to any one of Embodiments I-80 toI-137, wherein the method further comprises the step of suspendingadministration for a subsequent suspension period after completion ofthe suspension period and resumption of administration.

Embodiment I-139

The formulation for use according to Embodiment I-138, wherein thesubsequent suspension period occurs at least 12 weeks after resumingonce daily administration of the oral formulation comprising about 80 mgto about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment I-140

The formulation for use according to any one of Embodiments I-80 toI-139, wherein the prostate cancer is castration-resistant metastaticprostate cancer.

Embodiment I-141

The formulation for use according to any one of Embodiments I-80 toI-140, wherein the prostate cancer is castration-resistantnon-metastatic prostate cancer.

Embodiment I-142

The formulation for use according to any one of Embodiments I-80 toI-141, wherein the prostate cancer is hormone-sensitive metastaticprostate cancer.

Embodiment I-143

The formulation for use according to any one of Embodiments I-80 toI-142, wherein the prostate cancer is hormone-sensitive non-metastaticprostate cancer.

Embodiment I-144

Use ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of prostate cancer.

Embodiment I-145

The use according to Embodiment I-144, wherein the prostate cancer ishormone dependent prostate cancer.

Embodiment I-146

The use according to Embodiment I-144, wherein the prostate cancer isadvanced prostate cancer.

Embodiment I-147

The use according to Embodiment I-144, wherein the prostate cancer ismetastatic, non-metastatic, locally advanced, advanced hormonesensitive, advanced castration resistant, or recurrent.

Embodiment I-148

The use according to Embodiment I-144, wherein the prostate cancer iscastration-resistant metastatic prostate cancer.

Embodiment I-149

The use according to Embodiment I-144, wherein the prostate cancer iscastration-resistant non-metastatic prostate cancer.

Embodiment I-150

The use according to Embodiment I-144, wherein the prostate cancer ishormone-sensitive metastatic prostate cancer.

Embodiment I-151

The use according to Embodiment I-144, wherein the prostate cancer ishormone-sensitive non-metastatic prostate cancer.

Embodiment I-152

The use according to any one of Embodiments I-144 to I-151, wherein themedicament comprises 80 mg to about 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of the pharmaceutically acceptable saltthereof.

Some embodiments of this disclosure relate to Embodiment II, as follows:

Embodiment II-1

The method of any one of embodiments I-1 through I-78, wherein a PKprofile in which mean plasma AUC_((0-tau)) increases at least 1.5 foldwhen measured from the first to last day of administration is achieved.

Embodiment II-2

The method of any one of embodiments I-1 through I-78, wherein a PKprofile in which mean C_(max) increases at least 2 fold when measuredfrom the first to last day of administration is achieved.

Embodiment II-3

The method according to embodiment II-1, wherein the increase is atleast 1.5 fold is 2 fold or greater.

Embodiment II-4

The method of any one of embodiments II-1 through II-3, wherein theadministering is without any fasting requirement.

Embodiment II-5

The method of any one of embodiments II-1 through II-3, wherein meanC_(max) is higher with preprandial administration than with postprandialadministration.

Embodiment II-6

The method of any one of embodiments II-1 through II-3, wherein meanplasma AUC_((0-tau)) is higher with preprandial administration than withpostprandial administration after at least 30 minutes.

Embodiment II-7

The method of any one of embodiments I-1 through I-78 or embodimentsII-1 through II-6, wherein the oral formulation includes at least oneexcipient that improves stability while maintaining load capacity.

Embodiment II-8

The method of any one of embodiments I-1 through I-78 or embodimentsII-1 through II-7, wherein the oral formulation is a tablet.

Embodiment II-9

The method of any one of embodiments II-1 through II-3, wherein meanplasma T_(1/2) is about 37 to about 42 hours measured at the end ofadministration.

Embodiment II-10

The method of any one of embodiments II-1 through II-3, wherein meanC_(max) is achieved between 1 and 2 hours (T_(max)) after beginningadministration.

Embodiment II-11

The method of any one of embodiments II-1 through II-3, wherein steadystate is reached within 10 days after beginning administration.

Embodiment II-12

The method of any one of embodiments II-1 through II-3, whereinprostate-specific antigen (PSA) is suppressed in the subject to a levelless than or equal to 4 ng/mL.

Embodiment II-13

The method of any one of embodiments II-1 through II-3, whereinprostate-specific antigen (PSA) is suppressed in the subject to a levelless than or equal to 2 ng/mL.

Embodiment II-14

The method of any one of embodiments II-1 through II-3, wherein lessthan 4% of theN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaor a pharmaceutically acceptable salt thereof is excreted unchanged inurine of the subject, measured at day 14 or day 28 after commencingadministration.

Embodiment II-15

The method of any one of embodiments II-1 through II-3, wherein medicalcastration levels of less than or equal to 50 ng/dL (1.73 nmol/L) serumtestosterone are achieved and maintained from day 14 to day 28 aftercommencing administration.

Embodiment II-16

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily an oral load dose formulation of 360mg, or a corresponding amount of a pharmaceutically acceptable saltthereof, and oral maintenance dose formulations of 120 mg, or acorresponding amount of a pharmaceutically acceptable salt thereof, for48 consecutive weeks, medical castration levels of less than or equal to50 ng/dL (1.73 nmol/L) serum testosterone are achieved by the beginningof week 5 and maintained through the end of week 48.

Embodiment II-17

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 120 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 13 consecutive weeks, change from baselinein mean serum PSA concentration at the end of 13 consecutive weeks is a8 to 12 fold reduction for the 80 mg dose and a 9 to 13 fold reductionfor the 120 mg dose.

Embodiment II-18

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 120 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 25 consecutive weeks, median trough plasmaconcentration (C_(min)) of unchangedN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaor a pharmaceutically acceptable salt thereof ranges between 2.0 ng/mLand 8.0 ng/mL for the 80 mg dose and between 4.0 ng/mL and 12.0 ng/mLfor the 120 mg dose.

Embodiment II-19

The method of any one of embodiments II-1 through II-3, wherein theadministering results in C_(min) being maintained constant overadministration.

Embodiment II-20

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum luteinizing hormone (LH) concentration at the end of 16consecutive days is a 12 to 16 fold reduction for the 80 mg dose and a15 to 19 fold reduction for the 180 mg dose.

Embodiment II-21

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum testosterone concentration at the end of 16 consecutivedays is a 27 to 31 fold reduction for the 80 mg dose and a 22 to 26 foldreduction for the 180 mg dose.

Embodiment II-22

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum follicle stimulating hormone (FSH) concentration at theend of 16 consecutive days is a 7 to 11 fold reduction for the 80 mgdose and a 10 to 14 fold reduction for the 180 mg dose.

Embodiment II-23

The method of any one of embodiments II-1 through II-15, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum dihydrotestosterone (DHT) concentration at the end of 16consecutive days is a 1.1 to 3 fold reduction for the 80 mg dose and a1.1 to 4 fold reduction for the 180 mg dose.

Embodiment II-24

The method of any one of embodiments II-1 through II-3, wherein theadministering is such that there is no stimulation of sex hormones, andthereby clinical flare is prevented or minimized.

Embodiment II-25

A method for treating hormone dependent prostate cancer in a subject,the method comprising:

administering to the subject once-daily for at least one day for a firsttreatment period, an oral load dose formulation having from 240 mg to480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;

wherein the oral maintenance dose formulation has a PK profile in whichmean plasma AUC_((0-tau)) increases at least 1.5 fold when measured fromthe first day of the first treatment period to last day of the secondtreatment period.

Embodiment II-26

A method for treating hormone dependent prostate cancer in a subject,the method comprising:

administering to the subject once-daily for at least one day for a firsttreatment period, an oral load dose formulation having from 240 mg to480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and

administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;

wherein the oral maintenance dose formulation has a PK profile in whichmean C_(max) increases at least 2 fold when measured from the first dayof the first treatment period to last day of the second treatmentperiod.

Embodiment II-27

A method for suppressing one or more sex hormones in a subject havinghormone dependent prostate cancer, the method comprising:

administering to the subject once-daily for at least one day for a firsttreatment period, an oral load dose formulation having from 240 mg to480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and

administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;

wherein the oral maintenance dose formulation has a PK profile in whichmean plasma AUC_((0-tau)) increases at least 1.5 fold when measured fromthe first day of the first treatment period to last day of the secondtreatment period.

Embodiment II-28

A method for suppressing one or more sex hormones in a subject havinghormone dependent prostate cancer, the method comprising:

administering to the subject once-daily for at least one day for a firsttreatment period, an oral load dose formulation having from 240 mg to480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and

administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;

wherein the oral maintenance dose formulation has a PK profile in whichmean C_(max) increases at least 2 fold when measured from the first dayof the first treatment period to last day of the second treatmentperiod.

Embodiment II-29

The method of embodiments II-25 or II-27, wherein at least 1.5 fold is 2fold or greater.

Embodiment II-30

The method of any one of embodiments II-25 through II-29, wherein thefirst treatment period is 1 day or greater.

Embodiment II-31

The method of any one of embodiments II-25 through II-29, wherein thefirst treatment period is 2 days or greater.

Embodiment II-32

The method of any one of embodiments II-25 through II-29, wherein thefirst treatment period is 3 days or greater.

Embodiment II-33

The method of any one of embodiments II-25 through II-29, wherein thesecond treatment period is 52 consecutive weeks or greater.

Embodiment II-34

The method of any one of embodiments II-25 through II-29, wherein thesecond treatment period is 72 consecutive weeks or greater.

Embodiment II-35

The method of any one of embodiments II-25 through II-29, wherein thesecond treatment period is 96 consecutive weeks or greater.

Embodiment II-36

The method of any one of embodiments II-25 through II-29, wherein theadministering is preprandial.

Embodiment II-37

The method of any one of embodiments II-25 through II-29, wherein theadministering is at least 1 hour before eating or at least 2 hours aftereating.

Embodiment II-38

The method of any one of embodiments II-25 through II-29, wherein theadministering is at least 30 minutes before eating or while subject isfasting.

Embodiment II-39

The method of any one of embodiments II-25 through II-29, wherein theadministering is without any fasting requirement.

Embodiment II-40

The method of any one of embodiments II-25 through II-29, wherein meanC_(max) is higher with preprandial administration than with postprandialadministration.

Embodiment II-41

The method of any one of embodiments II-25 through II-29, wherein meanplasma AUC_((0-tau)) is higher with preprandial administration than withpostprandial administration after at least 30 minutes.

Embodiment II-42

The method of any one of embodiments II-25 through II-29, wherein theoral load dose formulation and the oral maintenance dose formulation aretablets.

Embodiment II-43

The method of any one of embodiments II-25 through II-29, wherein theoral load dose formulation and the oral maintenance dose formulationhave an immediate release profile.

Embodiment II-44

The method of any one of embodiments II-25 through II-29, wherein meanplasma T_(1/2) is about 37 to about 42 hours measured at the end ofadministration.

Embodiment II-45

The method of any one of embodiments II-25 through II-29, wherein meanC_(max) is achieved between 1 and 2 hours (T_(max)) after beginningadministration.

Embodiment II-46

The method of any one of embodiments II-25 through II-29, wherein steadystate is reached within 10 days after beginning administration.

Embodiment II-47

The method of any one of embodiments II-25 through II-29, wherein serumtestosterone is suppressed in the subject to a castration level that isless than or equal to 50 ng/dL (1.73 nmol/L).

Embodiment II-48

The method of any one of embodiments II-25 through II-29, wherein serumtestosterone is suppressed in the subject to a profound castration levelthat is less than or equal to 20 ng/dL (0.69 nmol/L).

Embodiment II-49

The method of any one of embodiments II-25 through II-29, whereinprostate-specific antigen (PSA) is suppressed in the subject to a levelless than or equal to 4 ng/mL.

Embodiment II-50

The method of any one of embodiments II-25 through II-29, whereinprostate-specific antigen (PSA) is suppressed in the subject to a levelless than or equal to 2 ng/mL.

Embodiment II-51

The method of any one of embodiments II-25 through II-29, wherein theoral load dose formulation is 240 mg, or 360 mg, or 480 mg, or acorresponding amount of a pharmaceutically acceptable salt thereof, andthe oral maintenance dose formulation is 80 mg, or 120 mg, or 160 mg, ora corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-52

The method of any one of embodiments II-25 through II-29, wherein theoral load dose formulation is 360 mg, or a corresponding amount of apharmaceutically acceptable salt thereof, and the oral maintenance doseformulation is 120 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof.

Embodiment II-53

The method of any one of embodiments II-25 through II-29, wherein theoral load dose formulation is 360 mg, or a corresponding amount of apharmaceutically acceptable salt thereof, and is administered on day 1of the first treatment period, and the oral maintenance dose formulationis 120 mg, or a corresponding amount of a pharmaceutically acceptablesalt thereof, administered starting on day 1 or day 2 of the secondtreatment period.

Embodiment II-54

The method of any one of embodiments II-25 through II-29, wherein lessthan 4% of theN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaor a pharmaceutically acceptable salt thereof is excreted unchanged inurine of the subject, measured at day 14 or day 29 after commencing thefirst treatment period.

Embodiment II-55

The method of any one of embodiments II-25 through II-28, whereinmedical castration levels of less than or equal to 50 ng/dL (1.73nmol/L) serum testosterone are achieved and maintained from day 14 today 28 after commencing treatment.

Embodiment II-56

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily a single oral load dose formulationof 360 mg, or a corresponding amount of a pharmaceutically acceptablesalt thereof, and oral maintenance dose formulations of 120 mg, or acorresponding amount of a pharmaceutically acceptable salt thereof, for48 consecutive weeks, medical castration levels of less than or equal to50 ng/dL (1.73 nmol/L) serum testosterone are achieved by the beginningof week 5 and maintained through the end of week 48.

Embodiment II-57

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 120 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 13 consecutive weeks, change from baselinein mean serum PSA concentration at the end of 13 consecutive weeks is a8 to 12 fold reduction for the 80 mg dose and a 9 to 13 fold reductionfor the 120 mg dose.

Embodiment II-58

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 120 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 25 consecutive weeks, median trough plasmaconcentration (C_(min)) of unchangedN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaor a pharmaceutically acceptable salt thereof ranges between 2.0 ng/mLand 8.0 ng/mL for the 80 mg dose and between 4.0 ng/mL and 12.0 ng/mLfor the 120 mg dose.

Embodiment II-59

The method of any one of embodiments II-25 through II-29, wherein theadministering results in C_(min) being maintained constant over thesecond treatment period.

Embodiment II-60

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum luteinizing hormone (LH) concentration at the end of 16consecutive days is a 12 to 16 fold reduction for the 80 mg dose and a15 to 19 fold reduction for the 180 mg dose.

Embodiment II-61

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum testosterone concentration at the end of 16 consecutivedays is a 27 to 31 fold reduction for the 80 mg dose and a 22 to 26 foldreduction for the 180 mg dose.

Embodiment II-62

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum follicle stimulating hormone (FSH) concentration at theend of 16 consecutive days is a 7 to 11 fold reduction for the 80 mgdose and a 10 to 14 fold reduction for the 180 mg dose.

Embodiment II-63

The method of any one of embodiments II-25 through II-29, whereinfollowing administering once-daily oral maintenance dose formulations of80 mg or 180 mg, or a corresponding amount of a pharmaceuticallyacceptable salt thereof, for 16 consecutive days, change from baselinein mean serum dihydrotestosterone (DHT) concentration at the end of 16consecutive days is a 1.1 to 3 fold reduction for the 80 mg dose and a1.1 to 4 fold reduction for the 180 mg dose.

Embodiment II-64

The method of any one of embodiments II-25 through II-29, wherein thesubject has advanced hormone dependent prostate cancer.

Embodiment II-65

The method of any one of embodiments II-25 through II-29, whereinadministering can be suspended for a period of 4 weeks or less to 24weeks or greater, after at least 24 consecutive weeks, ofadministration.

Embodiment II-66

The method of embodiment II-65, wherein, after administering issuspended, return to baseline serum testosterone levels in subjects isachieved within 4 weeks to 12 weeks, after the last dose.

Embodiment II-67

The method of embodiment II-65, wherein, after administering isrestarted, return to castration levels in subjects are achieved within24 hours to 48 hours.

Embodiment II-68

The method of any one of embodiments II-25 through II-29, wherein theadministering is such that there is no stimulation of sex hormones, andthereby clinical flare is prevented or minimized.

Embodiment II-69

The method of any one of embodiments II-25 through II-29, wherein theprostate cancer is advanced prostate cancer.

Embodiment II-70

The method of any one of embodiments II-25 through II-29, wherein thetreating is palliative and the prostate cancer is advanced prostatecancer.

Embodiment II-71

A dosage pack comprising:

a once-daily oral load dose formulation having from 240 mg to 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and excipients; and

a once-daily oral maintenance dose formulation having 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and excipients;

wherein the once-daily oral maintenance dose formulation has a PKprofile in which mean plasma AUC_((0-tau)) increases at least 1.5 foldwhen measured from the first to last day of a treatment period, whereinthe treatment period of the once-daily oral maintenance doseformulations is for 24 consecutive weeks or greater.

Embodiment II-72

A dosage pack comprising:

a once-daily oral load dose formulation having from 240 mg to 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and excipients; and a once-daily oral maintenance dose formulationhaving 80 mg to 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and excipients;

wherein the once-daily oral maintenance dose formulation has a PKprofile in which mean C_(max) increases at least 2 fold when measuredfrom the first to last day of a treatment period, wherein the treatmentperiod of the once-daily oral maintenance dose formulations is for 24consecutive weeks or greater.

Embodiment II-73

The dosage pack of embodiment II-71, wherein the at least 1.5 fold is 2fold or greater.

Embodiment II-74

The dosage pack of embodiment II-71 or II-72, wherein the oral load doseformulation comprises 306 mg to 612 mg of mannitol, 18 mg to 36 mg ofhydroxypropyl cellulose, 30 mg to 60 mg of sodium starch glycolate, and6 mg to 12 mg of magnesium stearate.

Embodiment II-75

The dosage pack of embodiment II-74, wherein the oral load doseformulation further comprises 21.36 mg to 42.72 mg of hypromellose 2910,2.4 mg to 4.8 mg of titanium dioxide, 0.24 mg to 0.48 mg of ferricoxide, and a sufficient quantity of carnauba wax.

Embodiment II-76

The dosage pack of embodiment II-71 or II-72, wherein the oralmaintenance dose formulation comprises 102 mg to 204 mg of mannitol, 6mg to 12 mg of hydroxypropyl cellulose, 10 mg to 20 mg of sodium starchglycolate, and 2 mg to 4 mg of magnesium stearate.

Embodiment II-77

The dosage pack of embodiment II-76, wherein the oral maintenance doseformulation further comprises 7.12 mg to 14.24 mg of hypromellose 2910,0.8 mg to 1.6 mg of titanium dioxide, 0.08 mg to 0.16 mg of ferricoxide, and a sufficient quantity of carnauba wax.

Embodiment II-78

The dosage pack of embodiment II-75 or II-77, wherein the oral load doseformulation and the oral maintenance dose formulation include at leastone excipient that improves stability while maintaining load capacity.

Embodiment II-79

The dosage pack of embodiment II-74 or II-76, wherein the sodium starchglycolate in the oral load dose formulation and the oral maintenancedose formulation improves stability and load capacity ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaor a pharmaceutically acceptable salt thereof in the oral load doseformulation and the oral maintenance dose formulation.

Embodiment II-80

The dosage pack of embodiment II-71 or II-72, wherein the oral load doseformulation has 240 mg, or 360 mg, or 480 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-81

The dosage pack of embodiment II-71 or II-72, wherein the oralmaintenance dose formulation has 80 mg, or 120 mg, or 160 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-82

The dosage pack of embodiment II-71 or II-72, wherein the oral load doseformulation has 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof,and the oral maintenance dose formulation has 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-83

The dosage pack of embodiment II-71 or II-72, wherein the oral load doseformulation and the oral maintenance dose formulation are tablets.

Embodiment II-84

The dosage pack of embodiment II-71 or II-72, wherein the oral load doseformulation and the oral maintenance dose formulation have an immediaterelease profile.

Embodiment II-85

The dosage pack of embodiment II-71 or II-72, further comprising atleast one of an anti-androgen or CYP17 lyase inhibitor.

Embodiment II-86

The dosage pack of embodiment II-85, wherein the anti-androgen comprisesenzalutamide, bicalutamide, enzalutamide or flutamide, and the CYP17lyase inhibitor comprises abiraterone.

Embodiment II-87

The dosage pack of embodiment II-71 or II-72, which is used for treatinghormone dependent prostate cancer.

1-152. (canceled)
 153. A method for treating prostate cancer in asubject in need thereof, the method comprising: administering to thesubject once-daily for at least one day for a first treatment period, anoral load dose formulation having 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;wherein the subject's follicle stimulating hormone (FSH) is less than orequal to about 2.4 mIU/mL after 24 consecutive weeks of treatment. 154.The method of claim 153, wherein profound castration is achieved. 155.The method of claim 154, wherein the profound castration is achievedwithin 24 to 48 hours after commencing administration and is maintaineduntil the end of administration.
 156. The method of claim 153, whereintime to castration resistance is longer than in a subject receiving GnRHagonist therapy.
 157. The method of claim 153, further comprisingadministering enzalutamide.
 158. A method for suppressing one or moresex hormones in a subject having hormone-dependent prostate cancer, themethod comprising: administering to the subject once-daily for at leastone day for a first treatment period, an oral load dose formulationhaving 360 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;and administering to the subject once-daily for 24 consecutive weeks orgreater for a second treatment period, an oral maintenance doseformulation having 120 mg ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a corresponding amount of a pharmaceutically acceptable salt thereof;wherein the oral maintenance dose formulation has a PK profile in whichmean plasma AUC(0-tau) increases at least 1.5 fold when measured fromthe first day of the first treatment period to last day of the secondtreatment period; wherein the sex hormone is FSH; and wherein thesubject's FSH is less than or equal to about 2.4 mIU/mL after 24consecutive weeks of treatment.
 159. The method of claim 158, whereinprofound castration is achieved.
 160. The method of claim 159, whereinthe profound castration is achieved within 24 to 48 hours aftercommencing administration and is maintained until the end ofadministration.
 161. The method of claim 158, wherein time to castrationresistance is longer than in a subject receiving GnRH agonist therapy.162. The method of claim 158, further comprising administeringenzalutamide.